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BIOMARKER:

MAP2K1 mutation

i
Other names: MAP2K1, MAPKK1, MEK1, PRKMK1, Mitogen-activated protein kinase kinase 1
Entrez ID:
Related biomarkers:
13d
Potential benefit of treatment with MEK inhibitors and chemotherapy in BRAF-mutated KRAS wild-type pancreatic ductal adenocarcinoma patients: a case report. (PubMed, Cold Spring Harb Mol Case Stud)
This is the first case report of a 60-yr-old female who underwent therapy for metastatic pancreatic cancer with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX). The patient has achieved a complete response (CR) to a combination of gemcitabine, nab-paclitaxel, and cobimetinib. It has been 16 mo since the start of the treatment, and the patient continues to demonstrate a complete durable response both serologically and radiologically.
Clinical • Journal
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BRAF (B-raf proto-oncogene) • KRAS (KRAS proto-oncogene GTPase) • MAP2K1 (Mitogen-activated protein kinase kinase 1) • MAP2K2 (Mitogen-activated protein kinase kinase 2)
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BRAF V600E • KRAS mutation • BRAF mutation • BRAF V600 • MAP2K1 mutation • RAS wild-type • KRAS wild-type • BRAF wild-type • BRAF V600 wild-type
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gemcitabine • 5-fluorouracil • Cotellic (cobimetinib) • Abraxane (albumin-bound paclitaxel) • oxaliplatin • irinotecan • leucovorin calcium
1m
A Basket Trial of an ERK1/2 Inhibitor (LY3214996) in Combination With Abemaciclib. (clinicaltrials.gov)
P2, N=35, Recruiting, Anita Turk | Trial completion date: Sep 2022 --> Sep 2023 | Trial primary completion date: Jun 2022 --> Jun 2023
Clinical • Trial completion date • Trial primary completion date • Combination therapy • Pan tumor
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BRAF (B-raf proto-oncogene) • MAP2K1 (Mitogen-activated protein kinase kinase 1) • NF1 (Neurofibromin 1)
|
BRAF V600E • BRAF V600 • NF1 mutation • MAP2K1 mutation • RAF1 amplification
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Verzenio (abemaciclib) • temuterkib (LY3214996)
3ms
Oncogenic KRAS promotes growth of lung cancer cells expressing SLC3A2-NRG1 fusion via ADAM17-mediated shedding of NRG1. (PubMed, Oncogene)
Taken together, this is the first study to report that KRAS mutation increased NRG1 cleavage from the S-N fusion protein through ADAM17, thereby enhancing the Ras/Raf/MEK/ERK and ERBB/PI3K/Akt/mTOR pathways. Moreover, the coexistence of KRAS mutant and S-N fusion in lung tumours renders them vulnerable to MEK1/2 and/or ADAM17 inhibitors, at least in part, due to their dependency on the strong positive loop between KRAS mutation and S-N fusion.
Journal
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EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • NRG1 (Neuregulin 1) • ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3) • SLC3A2 (Solute Carrier Family 3 Member 2) • ADAM17 (ADAM Metallopeptidase Domain 17)
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KRAS mutation • EGFR mutation • MAP2K1 mutation • MTOR mutation • NRG1 fusion • SLC3A2-NRG1 fusion • SLC3A2 expression • NRG1 fusion
3ms
[VIRTUAL] Targeting TRIBBLES1 (TRIB1) Pseudokinase as a New Therapeutic Approach in GBM (ASTRO 2021)
Our data suggest that TRIB1 is a potential therapeutic target for GBM therapy as targeting TRIB1 could promote treatment sensitizing glioma cells to RT/TMZ. Targeting MEK1 binding site on TRIB1 could also reduce MAPK oncogenic signaling in these cells thereby providing an additional treatment strategy for GBM.
MAP2K1 (Mitogen-activated protein kinase kinase 1)
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MAP2K1 mutation
3ms
Targeting TRIBBLES1 (TRIB1) Pseudokinase as a New Therapeutic Approach in GBM. (PubMed, Int J Radiat Oncol Biol Phys)
Our data suggest that TRIB1 is a potential therapeutic target for GBM therapy as targeting TRIB1 could promote treatment sensitizing glioma cells to RT/TMZ. Targeting MEK1 binding site on TRIB1 could also reduce MAPK oncogenic signaling in these cells thereby providing an additional treatment strategy for GBM.
Journal
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MAP2K1 (Mitogen-activated protein kinase kinase 1)
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MAP2K1 mutation
4ms
A Phase 1b / 2a, open-label platform study to evaluate mirdametinib in combination with fulvestrant in ER+ metastatic breast cancers harboring MAPK-activating mutations (SABCS 2021)
The primary endpoint for the study will be safety and tolerability of mirdametinib in combination with fulvestrant, and secondary endpoints include Overall Response Rate (ORR), Progression Free Survival (PFS), Clinical Benefit Rate (CBR), and Duration of Response (DOR) for the drug combination in each cohort and for the total study population. Overall survival is not an endpoint of this protocol.
Clinical • P1 data • Combination therapy
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EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • BRAF (B-raf proto-oncogene) • KRAS (KRAS proto-oncogene GTPase) • ER (Estrogen receptor) • HRAS (Harvey rat sarcoma viral oncogene homolog) • NF1 (Neurofibromin 1)
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KRAS mutation • EGFR mutation • HER-2 amplification • BRAF mutation • HER-2 mutation • EGFR amplification • HRAS mutation • MAP2K1 mutation • ER expression
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fulvestrant • mirdametinib (PD-0325901)
4ms
Clinical • New P1 trial • Combination therapy
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HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • MAP2K1 (Mitogen-activated protein kinase kinase 1) • NF1 (Neurofibromin 1) • MAP2K2 (Mitogen-activated protein kinase kinase 2)
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HR positive • ER positive • HER-2 negative • MAP2K1 mutation • MAP2K1 P124L • MAP2K1 P124S • MAP2K2 mutation • MAP2K1 C121S • MAP2K1 F53L • MAP2K1 K57N • MAP2K1 P124
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fulvestrant • mirdametinib (PD-0325901)
5ms
A Basket Trial of an ERK1/2 Inhibitor (LY3214996) in Combination With Abemaciclib. (clinicaltrials.gov)
P2, N=35, Recruiting, Anita Turk | Trial primary completion date: Sep 2021 --> Jun 2022
Clinical • Trial primary completion date • Combination therapy • Pan tumor
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BRAF (B-raf proto-oncogene) • MAP2K1 (Mitogen-activated protein kinase kinase 1) • NF1 (Neurofibromin 1)
|
BRAF V600E • BRAF V600 • NF1 mutation • MAP2K1 mutation • RAF1 amplification
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Verzenio (abemaciclib) • temuterkib (LY3214996)
6ms
Kirsten rat sarcoma viral oncogene homolog G12C mutant advanced non-small-cell lung cancer treated with MEK1/2 inhibitor trametinib: a case report. (PubMed, Anticancer Drugs)
Furthermore, this report reviewed the previous date of the preclinical and clinical and summarized that KRAS G12C mutation may be more sensitive to the inhibition of mitogen-activated protein kinase kinase. This case advocates for routine screening of KRAS point mutations in the utility of precision medicine and suggests that treatment with trametinib in advanced NSCLC cases with KRAS G12C mutation is well tolerated and effective, especially for those very elderly or unsuitable for more aggressive chemotherapy.
Preclinical • Journal
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KRAS (KRAS proto-oncogene GTPase)
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KRAS mutation • KRAS G12C • MAP2K1 mutation • KRAS G12
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Mekinist (trametinib)
6ms
Antitumor efficacy of XPO1 inhibitor Selinexor in KRAS-mutant lung adenocarcinoma patient-derived xenografts. (PubMed, Transl Oncol)
Monotherapy with Selinexor reduced tumor growth in all KRAS PDXs, which included 4 different codon mutations, and was more effective than the clinical MEK1/2 inhibitor, Trametinib. However, targeted kinase inhibitors were more effective than Selinexor in these models. Our findings support continued investigation of XPO1 inhibitors in KRAS lung adenocarcinoma, regardless of the codon alteration.
Clinical • Journal • IO biomarker
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KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • XPO1 (Exportin 1)
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TP53 mutation • KRAS mutation • MAP2K1 mutation
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Mekinist (trametinib) • Xpovio (selinexor)
7ms
Dual targeting of MEK and PI3K effectively controls the proliferation of human EGFR-TKI resistant non-small cell lung carcinoma cell lines with different genetic backgrounds. (PubMed, BMC Pulm Med)
Dual targeting regulated the proliferation of EGFR-TKI-resistant NSCLC cells, especially mutants in K-RAS and PIK3CA that are promising for EGFR-TKI-resistant NSCLC therapeutics.
Preclinical • Journal
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EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • EIF4EBP1 (Eukaryotic translation initiation factor 4E binding protein 1)
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KRAS mutation • EGFR mutation • PIK3CA mutation • MET amplification • MAP2K1 mutation • KRAS amplification • EGFR H1975 • PIK3CA mutation + KRAS mutation
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Gilotrif (afatinib) • Mektovi (binimetinib) • buparlisib (BKM120) • tivantinib (ARQ 197)
7ms
High tumour mutational burden and EGFR/MAPK pathway activation are therapeutic targets in metastatic porocarcinoma. (PubMed, Br J Dermatol)
Molecular profiling demonstrated high tumour mutational burden and EGFR/MAPK pathway activation as novel therapeutic targets in mEPC.
Journal • Tumor Mutational Burden • IO biomarker
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TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • MAP2K1 (Mitogen-activated protein kinase kinase 1) • CDKN2A (Cyclin-dependent kinase inhibitor 2A)
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TP53 mutation • TMB-H • EGFR mutation • EGFR overexpression • CDKN2A deletion • MAP2K1 mutation
8ms
NGS-based liquid-biopsy profiling identifies mechanisms of resistance to ALK inhibitors: a step towards personalized NSCLC treatment. (PubMed, Mol Oncol)
Finally, a c-MYC gain, along with a loss of CCND1 and FGFR3, were detected in a patient progressing on a first-line treatment with crizotinib. We conclude that NGS analysis of liquid biopsies upon disease progression identified different putative ALK-I-resistance mutations in most cases, and could be a valuable approach for therapy decision making.
Journal • Liquid biopsy • Next-generation sequencing
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EGFR (Epidermal growth factor receptor) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • FGFR2 (Fibroblast growth factor receptor 2) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • FGFR3 (Fibroblast growth factor receptor 3) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • MAP2K1 (Mitogen-activated protein kinase kinase 1) • CCND1 (Cyclin D1) • SMAD4 (SMAD family member 4) • CCND3 (Cyclin D3)
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TP53 mutation • EGFR mutation • BRAF mutation • PIK3CA mutation • EGFR exon 19 deletion • ALK positive • FGFR2 mutation • ALK mutation • MAP2K1 mutation • ALK G1202R • ALK G1269A • BRAF G466V • MAP2K1 F129L
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Xalkori (crizotinib)
9ms
[VIRTUAL] Molecular characterization of the Ras-MAPK pathway in metastatic breast cancer. (ASCO 2021)
Our study demonstrates that RAS, BRAF and MEK1 mutations are associated with MAPK pathway activation indicative of benefit from MEKi or BRAFi . GMAT warrant further investigation for combinations targeting the RAS-MAPK pathway and immune checkpoint inhibitors.
Tumor Mutational Burden • PD(L)-1 Biomarker • IO biomarker
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PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog) • MAP2K1 (Mitogen-activated protein kinase kinase 1) • ARID1A (AT-rich interaction domain 1A) • PIK3R1 (Phosphoinositide-3-Kinase Regulatory Subunit 1) • MSH3 (MutS Homolog 3) • PRKDC (Protein Kinase, DNA-Activated, Catalytic Subunit)
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PD-L1 expression • KRAS mutation • MSI-H/dMMR • BRAF mutation • BRAF V600 • PIK3CA mutation • KRAS G12C • HRAS mutation • MAP2K1 mutation • KRAS G12 • NRAS G12 • NRAS Q61 • KRAS Q61 • HRAS G12C • PIK3R1 mutation
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MI Tumor Seek™
9ms
The transcription factor Slug uncouples pancreatic cancer progression from the Raf-Mek1/2-Erk1/2 pathway. (PubMed, Cancer Res)
Slug was targeted using two independent strategies: i) inhibition of the Mek5-Erk5 pathway, which is responsible for upregulation of Slug upon Mek1/2 inhibition, and ii) direct PROTAC-mediated degradation. Both strategies were efficacious in preclinical pancreatic cancer models, paving the path for the development of more effective therapies against pancreatic cancer.
Journal
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BRAF (B-raf proto-oncogene) • KRAS (KRAS proto-oncogene GTPase) • MAP2K1 (Mitogen-activated protein kinase kinase 1)
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BRAF mutation • MAP2K1 mutation
9ms
Bone Morphogenic Protein Signaling and Melanoma. (PubMed, Curr Treat Options Oncol)
They control transcription and epigenetic landscape of melanoma cells. Better understanding of the role of BMPs may lead to new strategies to control EMT processes in melanocyte cell lineage and to achieve clinical benefits for the patients.
Review • Journal • IO biomarker
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BRAF (B-raf proto-oncogene) • MAP2K1 (Mitogen-activated protein kinase kinase 1) • TGFB1 (Transforming Growth Factor Beta 1)
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BRAF mutation • MAP2K1 mutation
10ms
Allosteric Kinase Inhibitors Reshape MEK1 Kinase Activity Conformations in Cells and In Silico. (PubMed, Biomolecules)
Application of the allosterically acting MEK inhibitors (MEKi) trametinib, cobimentinib, refametinib, and selumetinib converted activated MEK1 KinCon reporters back into a more closed inactive conformation. We observed increased dynamics for the S218D/S222D double mutant particularly in the region of the distal A-helix and alpha-C helix. These data underline that MEK1 KinCon biosensors have the potential to be subjected to MEKi efficacy validations in an intact cell setting.
Journal
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BRAF (B-raf proto-oncogene) • MAP2K1 (Mitogen-activated protein kinase kinase 1)
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BRAF V600E • BRAF V600 • MAP2K1 mutation • MAP2K1 S218D • MAP2K1 S222D
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Mekinist (trametinib) • Koselugo (selumetinib) • refametinib (BAY86-9766)
10ms
PADI2-Catalyzed MEK1 Citrullination Activates ERK1/2 and Promotes IGF2BP1-Mediated SOX2 mRNA Stability in Endometrial Cancer. (PubMed, Adv Sci (Weinh))
Finally, PADI2 gene silencing, inhibiting MEK1 citrullination by PADI2 inhibitor, or mutation of MEK1 R113/189 equally inhibits EC progression. These data demonstrate that PADI2-catalyzed MEK1 R113/189 citrullination is a critical diver for EC malignancies and suggest that targeting PADI2/MEK1 can be a potential therapeutic approach in patients with EC.
Journal
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MAP2K1 (Mitogen-activated protein kinase kinase 1) • IGF2 (Insulin-like growth factor 2) • SOX2
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MAP2K1 mutation
10ms
FGFR2 fusion proteins drive oncogenic transformation of mouse liver organoids towards cholangiocarcinoma. (PubMed, J Hepatol)
FF-driven iCCA pathogenesis was successfully modeled in murine Tp53background, revealing biological heterogeneity among structurally different FFs. Double blockade of FF-Erk signaling deserves consideration for precision-based approaches against human FF iCCA.
Preclinical • Journal
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TP53 (Tumor protein P53) • FGFR2 (Fibroblast growth factor receptor 2) • CDKN2A (Cyclin-dependent kinase inhibitor 2A) • BAP1 (BRCA1 Associated Protein 1)
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TP53 mutation • FGFR2 mutation • FGFR2 fusion • BAP1 mutation • MAP2K1 mutation • TP53 expression
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Mekinist (trametinib) • Truseltiq (infigratinib)
11ms
[VIRTUAL] Repotrectinib increases effectiveness of MEK inhibitors in KRAS mutant cancer models (AACR 2021)
However, clinical studies of single agent MEKi or combinations with docetaxel in mutant KRAS NSCLC patients were associated with low response rates...Repotrectinib is a next-generation ROS1/TRK inhibitor with SRC/FAK/JAK2 inhibitory potencies which may suppress adaptive resistance to MEK inhibitors. In the current study, repotrectinib combinations with KRAS signaling network inhibitors including MEK (trametinib, selumetinib), MEK/RAF (VS-6766), ERK (LY3214996), SHP2 (TNO155) were explored...Repotrectinib was shown to suppress molecular mechanisms of adaptive resistance mechanisms to MEK inhibition in preclinical models. These results suggest that the combination of repotrectinib with MEKi can repress the mutant KRAS signaling network to achieve more potent and durable anti-tumor activity and warrants clinical investigation in patients with KRASG12D and KRASG12V mutant cancers.
Preclinical • PARP Biomarker
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KRAS (KRAS proto-oncogene GTPase) • MAP2K1 (Mitogen-activated protein kinase kinase 1)
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KRAS mutation • KRAS G12D • KRAS G12V • KRAS G13D • MAP2K1 mutation • KRAS G12
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Mekinist (trametinib) • docetaxel • Koselugo (selumetinib) • repotrectinib (TPX-0005) • VS-6766 • temuterkib (LY3214996) • FAK-JAK 2 dual Inhib • TNO-155
11ms
[VIRTUAL] CDK4 copy number gain in BRAF V600E-mutated non-small cell lung cancers resistant to dabrafenib plus trametinib (AACR 2021)
We highlight CDK4 copy number gain as a possible clinical resistant mechanism for DT therapies in BRAF V600E-mutated NSCLC. We are currently investigating how CDK4 contribute as the acquired resistance.
BRAF (B-raf proto-oncogene) • KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • PTEN (Phosphatase and tensin homolog) • MAP2K1 (Mitogen-activated protein kinase kinase 1) • CCND1 (Cyclin D1) • CDK4 (Cyclin-dependent kinase 4)
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BRAF V600E • KRAS mutation • NRAS mutation • BRAF V600 • MAP2K1 mutation • BRAF K601E • CCND1 expression • CDK4 overexpression • CCND1 expression + CDK4 expression • BRAF K601 • CDK4 mutation
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Mekinist (trametinib) • Tafinlar (dabrafenib)
11ms
Allosteric and ATP-Competitive MEK-Inhibition in a Novel Spitzoid Melanoma Model with a RAF- and Phosphorylation-Independent Mutation. (PubMed, Cancers (Basel))
In vivo, trametinib but not MAP855 significantly reduced tumor growth in the intrapleural model. To the best of our knowledge, this is the first patient-derived melanoma model with RAF- and phosphorylation-independent MEK mutation and we demonstrated its sensitivity to trametinib.
Journal
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MAP2K1 (Mitogen-activated protein kinase kinase 1)
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MAP2K1 mutation
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Mekinist (trametinib)
1year
Computational Study on the Effect of Inactivating/Activating Mutations on the Inhibition of MEK1 by Trametinib. (PubMed, Int J Mol Sci)
Hence, trametinib could dissociate from the active mutants (P124S and E203K) more easily compared with the WT MEK1. In summary, our theoretical results demonstrated that the active mutations may attenuate the inhibitory effects of MEK inhibitor (trametinib) on MEK1, which could be crucial clues for future anti-cancer treatment.
Journal
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EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • EML4 (EMAP Like 4)
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KRAS mutation • ALK positive • MAP2K1 mutation • MAP2K1 P124S • MAP2K1 E203K • MAP2K1 P124 • EGFR positive
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Mekinist (trametinib)
1year
[VIRTUAL] FGFR2 fusion protein-driven mouse models of intrahepatic cholangiocarcinoma unveil a necessary role for Erk signaling (DLCS 2021)
FF-driven iCCA pathogenesis was successfully modeled in murine Tp53-/-background, revealing biological heterogeneity among structurally different FFs. Double blockade of FF-Erk signaling deserves consideration for improving on precision-based approaches against human FF+ iCCA.
Preclinical
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TP53 (Tumor protein P53) • FGFR2 (Fibroblast growth factor receptor 2) • CDKN2A (Cyclin-dependent kinase inhibitor 2A) • BAP1 (BRCA1 Associated Protein 1)
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TP53 mutation • FGFR2 mutation • FGFR2 fusion • BAP1 mutation • MAP2K1 mutation • TP53 expression
1year
Tubeimoside I Inhibits Cell Proliferation and Induces a Partly Disrupted and Cytoprotective Autophagy Through Rapidly Hyperactivation of MEK1/2-ERK1/2 Cascade via Promoting PTP1B in Melanoma. (PubMed, Front Cell Dev Biol)
Besides, we also observed that TBMS1 treatment induced a partly disrupted autophagy, which still remained a protective role, disruption of which by chloroquine (CQ) or 3-methyladenine (3-MA) enhanced TBMS1-induced cell proliferation inhibition...These results indicated that TBMS1 might activate PTP1B, which further hyperactivates MEK1/2-ERK1/2 cascade, thereby inhibiting cell proliferation in melanoma. Our results provided the potentiality of TBMS1 as a drug candidate for melanoma therapy and confirmed that rapidly hyperactivating an oncogenic signaling pathway may also be a promising strategy for cancer treatment.
Journal
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BRAF (B-raf proto-oncogene) • MAP2K1 (Mitogen-activated protein kinase kinase 1)
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BRAF V600E • BRAF V600 • MAP2K1 mutation
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chloroquine phosphate
1year
Circulating Tumour DNA Sequencing Identifies a Genetic Resistance-Gap in Colorectal Cancers with Acquired Resistance to EGFR-Antibodies and Chemotherapy. (PubMed, Cancers (Basel))
Our results support the utility of ctDNA-Seq to guide treatment allocation for patients with resistance and the importance of investigating further non-canonical EGFR-Ab resistance mechanisms, such as microenvironmentally-mediated resistance. The detection of MAP2K1 mutations could inform trials of MEK-inhibitors in these tumours.
Journal
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EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • MAP2K1 (Mitogen-activated protein kinase kinase 1)
|
KRAS mutation • HER-2 amplification • HER-2 mutation • MAP2K1 mutation • MAP2K1 P124S • MAP2K1 P124
1year
A Basket Trial of an ERK1/2 Inhibitor (LY3214996) in Combination With Abemaciclib. (clinicaltrials.gov)
P2, N=35, Recruiting, Anita Turk | Not yet recruiting --> Recruiting
Clinical • Enrollment open • Combination therapy • Pan tumor
|
BRAF (B-raf proto-oncogene) • MAP2K1 (Mitogen-activated protein kinase kinase 1) • NF1 (Neurofibromin 1)
|
BRAF V600E • BRAF V600 • NF1 mutation • MAP2K1 mutation • RAF1 amplification
|
Verzenio (abemaciclib) • temuterkib (LY3214996)
over1year
[VIRTUAL] MEK1/2 Inhibition as a Therapeutic Target in an NRAS-Mutated Pediatric Neuroendocrine Tumor (ACS-CLINCON 2020)
Trametinib, a MEK1/2 inhibitor, significantly decreased tumor cell viability and growth both in vitro and in vivo through downregulation of cell proliferation signaling and an upregulation of apoptotic signaling. Decreased cell motility highlights an investigable role for trametinib in preventing metastasis. These studies provide preclinical justification for targeting MEK1/2 in NRAS-mutated pediatric solid tumors.
Clinical • PARP Biomarker
|
NRAS (Neuroblastoma RAS viral oncogene homolog) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • CASP3 (Caspase 3)
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NRAS mutation • MAP2K1 mutation • MYC expression
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Mekinist (trametinib)
over1year
Mechanisms of Acquired BRAF Inhibitor Resistance in Melanoma: A Systematic Review. (PubMed, Cancers (Basel))
BRAF inhibitor-resistant cells develop a range of 'escape routes', so multiple different treatment targets will probably be required to overcome resistance. In the future, it may be possible to personalize combination therapy towards the specific resistance pathway in individual patients.
Review • Journal
|
BRAF (B-raf proto-oncogene) • PD-L1 (Programmed death ligand 1) • NRAS (Neuroblastoma RAS viral oncogene homolog) • MAP2K1 (Mitogen-activated protein kinase kinase 1)
|
BRAF mutation • NRAS mutation • MAP2K1 mutation • BRAF amplification
over1year
Clinical • New P2 trial • Combination therapy • Pan tumor
|
BRAF (B-raf proto-oncogene) • MAP2K1 (Mitogen-activated protein kinase kinase 1) • NF1 (Neurofibromin 1)
|
BRAF V600E • BRAF V600 • NF1 mutation • MAP2K1 mutation • RAF1 amplification
|
Verzenio (abemaciclib) • temuterkib (LY3214996)
over1year
KRAS G12V Mutation in Acquired Resistance to Combined BRAF and MEK Inhibition in Papillary Thyroid Cancer. (PubMed, J Natl Compr Canc Netw)
The KRAS mutation was also detected in peripheral blood samples taken as part of the trial, indicating that resistant mutations may be identified through noninvasive means. The identification of resistant mutations in patients at time of progression is necessary to identify possible therapeutic options including potential clinical trials.ClinicalTrials.gov identifier: NCT01723202.
Journal
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BRAF (B-raf proto-oncogene) • KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • MAP2K1 (Mitogen-activated protein kinase kinase 1) • RAC1 (Rac Family Small GTPase 1)
|
BRAF V600E • KRAS mutation • BRAF mutation • NRAS mutation • BRAF V600 • KRAS G12V • MAP2K1 mutation • KRAS G12
|
Cabometyx (cabozantinib tablet)
over1year
V211D mutation in MEK1 causes resistance to MEK inhibitors in colon cancer. (PubMed, Cancer Discov)
We report the emergence of the novel MEK1 gatekeeper mutation in a patient with BRAF colon cancer treated with the allosteric MEK inhibitor binimetinib and the anti-EGFR antibody panitumumab. Moreover, the mutant exhibits reduced sensitivity to all the allosteric MEK inhibitors tested. Thus this mutation serves as a general resistance mutation for current MEK inhibitors; however, it is sensitive to a newly reported ATP-competitive MEK inhibitor, which therefore could be used to overcome drug resistance.
Journal
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BRAF (B-raf proto-oncogene) • MAP2K1 (Mitogen-activated protein kinase kinase 1)
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BRAF mutation • MAP2K1 mutation • MAP2K1 V211D
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Vectibix (panitumumab) • Mektovi (binimetinib)
over1year
Melanoma with in-frame deletion of MAP2K1: a distinct molecular subtype of cutaneous melanoma mutually exclusive from BRAF, NRAS, and NF1 mutations. (PubMed, Mod Pathol)
In-frame deletions in MAP2K1, previously shown in experimental models to be strongly MAPK-activating, characterized a significant subset of triple wild-type melanoma (2.0%), suggesting a primary oncogenic role for these mutations. Comprehensive genomic profiling of melanomas enables detection of this alteration, which may have implications for potential therapeutic options.
Journal • Tumor Mutational Burden
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BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • NRAS (Neuroblastoma RAS viral oncogene homolog) • PTEN (Phosphatase and tensin homolog) • MAP2K1 (Mitogen-activated protein kinase kinase 1) • CDKN2A (Cyclin-dependent kinase inhibitor 2A) • NF1 (Neurofibromin 1) • CTNNB1 (Catenin (cadherin-associated protein), beta 1)
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TP53 mutation • BRAF mutation • NF1 mutation • MAP2K1 mutation • CDKN2A mutation + TP53 mutation
over1year
[VIRTUAL] Chloroquine synergizes with MEK1/2 targeted therapy through dual YAP and lysosomal inhibition in GNAQ/11 mutant uveal melanoma (AACR-II 2020)
Metastatic uveal melanoma is refractory to all forms of pharmacologic treatment, such as FDA-approved targeted therapies inhibiting MEK1/2 (i.e. trametinib and binimetinib). These findings were also recapitulated in an immunocompetent mouse model in which immortalized mouse melanocytes (Melan-A) with either a GNAQ or GNA11 activating mutation were implanted into syngeneic C57BL/6 mice. Our findings identify a novel mechanism of chloroquine and suggest a potentially effective strategy combining two FDA-approved drugs for the treatment of metastatic uveal melanoma.
GNAQ (G Protein Subunit Alpha Q) • GNA11 (G Protein Subunit Alpha 11)
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MAP2K1 mutation
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Mekinist (trametinib) • Mektovi (binimetinib)
over1year
Co-occurrence of targetable mutations in Non-small cell lung cancer (NSCLC) patients harboring MAP2K1 mutations. (PubMed, Lung Cancer)
Our analysis shows that MAP2K1-mutated NSCLC patients might frequently present with potentially targetable aberrations. Their role in providing resistance in these subtypes and the possible therapeutic opportunities justify further analyses of this rare NSCLC subgroup.
Clinical • Journal
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EGFR (Epidermal growth factor receptor) • BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • MAP2K1 (Mitogen-activated protein kinase kinase 1) • KEAP1 (Kelch Like ECH Associated Protein 1)
|
TP53 mutation • BRAF V600E • EGFR mutation • BRAF V600 • KEAP1 mutation • ROS1 rearrangement • MAP2K1 mutation
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pemetrexed
almost2years
Phase I Trial of Trametinib with Neoadjuvant Chemoradiation in Patients with Locally Advanced Rectal Cancer. (PubMed, Clin Cancer Res)
The combination of trametinib with 5FU-CRT is safe and well-tolerated, and may warrant additional study in a phase II trial, perhaps in a RAS/RAF-mutant selected population.
Clinical • P1 data • Journal
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BRAF (B-raf proto-oncogene) • KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog)
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BRAF mutation • MAP2K1 mutation
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Mekinist (trametinib) • fluorouracil topical
almost2years
The effect of MEK1/2 inhibitors on cisplatin-induced acute kidney injury (AKI) and cancer growth in mice. (PubMed, Cell Signal)
The effect of U0126 to decrease AKI may be mediated by inhibition of heat shock protein 1, CDK4 or stratifin (14-3-3σ). Trametinib was more effective than cisplatin in decreasing tumor growth, but unlike cisplatin, trametinib did not cause AKI.
Preclinical • Journal • PD(L)-1 Biomarker
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PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase) • CDK4 (Cyclin-dependent kinase 4) • CASP3 (Caspase 3)
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KRAS mutation • MAP2K1 mutation
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cisplatin • Mekinist (trametinib) • U0126
almost2years
MAPK pathway alterations correlate with poor survival and drive resistance to therapy in patients with lung cancers driven by ROS1 fusions. (PubMed, Clin Cancer Res)
We demonstrate that the activation of MAPK pathway is mechanisms of innate or acquired resistance and that patients harboring ROS1 fusion and concurrent MAPK alterations have worse survival. Our findings suggest a treatment strategy to target both aberrations.
Clinical • Journal
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CD74 (CD74 Molecule) • SLC34A2 (Solute carrier family 34 member 2)
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NF1 mutation • ROS1 positive • ROS1 fusion • MAP2K1 mutation • CA9 expression