MAP2K1 mutation

Focal post-radiation necrosis at site of an irradiated brain metastasis developed 9 months after SRS and is successfully being treated with low-dose bevacizumab. This illustrates the utility of NGS profiles that include class-1/2 MAP2K1-mutations in patients with melanoma and other malignancies to provide valuable information on a potentially active individualized treatment option. A prospective clinical trial that further evaluates the efficacy of MEK-inhibitor therapies in MAP2K1-mutated tumors is justified.

The MEK1/2 inhibitors in combination with other kinase (BRaf/KRas/PI3K) inhibitors showed significant anti-proliferative activity. Other combination of MEK inhibitor with PD-1, DYRK1, EGFR, BTK and/or VEGF inhibitors etc. showed promising results in many cancers including colorectal, pancreatic, gastrointestinal, solid tumor, breast cancer, melanoma and multiple myeloma etc. The dual or multi-targeted approaches of these combinations showed better and precise treatment of patients with resistant cancer.

Preliminary results of the MatchMel study revealed a variety of molecular mutations in WT melanoma pts. NF1 alterations appeared to be linked with Hi-TMB, which was associated with response to immunotherapy.

P2, N=165, Recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Oct 2028

We tracked ERV activation to the early induction of the transcription factor ELF3, which extensively bound and activated nonsilenced retroelements and synergized with IRF1 (interferon regulatory factor 1) in the activation of IFNs and IFN-stimulated genes. Trametinib-induced viral mimicry in PDAC may be exploited in the rational design of combination therapies in immuno-oncology.

Here we describe cell lines that exhibit doxycycline-dependent expression KRASG12V or BRAFV600E and harbour a stably integrated EGR1:EmGFP reporter gene that can be detected by flow cytometry, high-content microscopy or immunoblotting...Finally, substitution of EmGFP for a bacterial nitroreductase gene allowed KRASG12V or BRAFV600E to drive cell death in the presence of a pro-drug, which may allow selection of pathway inhibitors that promote survival. These cell lines should prove useful for cell-based screens to identify new regulators of KRAS- or BRAF-dependent ERK1/2 signalling (drug target discovery) as well as screening or triaging 'hits' from drug discovery screens.

P2, N=16, Terminated, Anita Turk | N=35 --> 16 | Trial completion date: Jul 2024 --> Aug 2023 | Recruiting --> Terminated | Trial primary completion date: Jun 2024 --> Aug 2023; Lack of efficacy.

These findings warrant further studies of clinical applications of MEK1/2 inhibitors and KRAS as 'actionable target' of cisplatin-based chemotherapy for glioblastoma.

The mutations alter residue-level internal molecular correlations by differentially prioritizing different conformational states, delineating the various modes of MEK1 activation reminiscent of a gear-shifting mechanism. We define the molecular basis of conversion of this kinase from its inactive to its active state, connecting structure, dynamics, and function by delineating the energy landscape and conformational plasticity, thus augmenting our understanding of MEK1 regulation.

Cobimetinib demonstrates robust efficacy in HN irrespective of underlying MAPK pathway mutation, including BRAF-wt and BRAFV600-mutant HN. Safety of cobimetinib in this patient population was consistent with the known safety profile.

P1b, N=6, Completed, Memorial Sloan Kettering Cancer Center | Active, not recruiting --> Completed | Trial completion date: Sep 2027 --> Oct 2023 | Trial primary completion date: Sep 2027 --> Oct 2023

MEKi, selumetinib and trametinib, represent promising strategies in children with recurrent/progressive LGGs harboring MAPK alterations. In our small series, the treatment was effective and well tolerable in patients with localized disease and without other risk factors. The most common toxicities were CPK elevation and rash.

The approval of the combination therapy of a BRAF inhibitor dabrafenib with the MEK1/2 inhibitor trametinib has improved the overall survival of ATC patients...We have previously demonstrated combined inhibition of Src with dasatinib and MEK1/2 with trametinib synergistically inhibits growth and induces apoptosis in BRAF- and RAS-mutant thyroid cancer cells, however PIK3CA-mutant cells exhibit a mixed response...Furthermore, combined inhibition of PDK1 and MEK1/2 was sufficient to reduce cell viability. These data indicate PDK1 inhibition is a therapeutic option for PIK3CA mutations that do not respond to combined Src and MEK1/2 inhibition.

Sensitivity to Trametinib (MEK1/2 inhibitor) and SCH772984 (ERK inhibitor) were significantly associated with higher TMB values (p < 0.05). Ruxolitinib demonstrated higher effectiveness in IL-6 dependent myeloma cell lines (p < 0.003). Presence of DDR protein (tp53, ATR, ATM) mutations were associated with higher Drug Sensitivity scores in Nutlin-3a, UMI77, and Doxorubicin (p < 0.05)... Our study underscores the significance of establishing ex vivo drug response panels in addition to NGS and immunochemistry data to advance precision medicine approaches in multiple myeloma. Addressing potential vulnerabilities created by common mechanisms of resistance may be more widely applicable than targeting rare activating mutations in RRMM. Therefore, by leveraging targeted therapy, patients can achieve favourable treatment responses, thus enabling them to gain access to subsequent immunotherapy options and maximize their therapeutic benefits.

In a fraction of patients, histologic transformation can also contribute to the development of acquire resistance. We provided a comprehensive overview of the mechanisms that limit the efficacy of this G12i and reviewed potential strategies to overcome and possibly delay the development of resistance in patients receiving KRAS directed targeted therapies.

P1b, N=6, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting | N=150 --> 6

P1b, N=150, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Sep 2024 --> Sep 2027 | Trial primary completion date: Sep 2024 --> Sep 2027

The RAS-MAPK pathway is activated in LCH and up to 60% can have a BRAF V600 mutation and can respond well to Vemurafenib (a BRAF V600 inhibitor)...She was commenced on subcutaneous Cytarabine (100 g/m 2 ) but this was complicated by neutropenic sepsis and did not improve her skin lesions. She was switched to oral Methotrexate at 20 mg weekly but this was stopped due to acute transaminitis and failure to respond...She had a re-challenge at the same dose Trametinib and prophylactic dose Lymecycline with good effect...Side effects include dermatitis acneiform which was straightforward to manage. Patients would require LV function monitoring by echocardiography or MUGA scan while on treatment.

In-vitro data showed the similar on-target enzyme activity of ABM-168 to marketed MEK inhibitors, as well as high anti-proliferation activities (IC50 <30nM) in multiple cancer cell lines with BRAF or RAS or NF1 mutation like A375, Colo-829, HT-29, MiaPaca-2, LN-229 etc. In vivo pharmacology studies demonstrated that ABM-168 had good potencies of tumor growth inhibitions with oral dose alone or combo with other drugs or compounds in multiple xenograft cancer models: In an A375-luc intracardiac melanoma metastatic model, ABM-168 at 2 mg/kg PO BID demonstrated an antitumor activity comparable to ABM-1310 (A highly BBB-permeable BRAF inhibitor developed by ABM Therapeutics) at different dose levels and frequencies. Single-dose, seven-day repeat dose non-GLP studies and four-week GLP toxicity studies in SD rats and beagle dogs were all completed. Based on these supportive preclinical study results, the IND of ABM-168 was submitted in 2022 Q3 to investigate its safety in human, which will be followed by further clinic development as a single agent, or in combination with other molecules to treat advanced cancers resulted from the abnormal MAPK signal pathway, particularly with brain tumors.

Overall, dabrafenib monotherapy or in combination with trametinib demonstrated clinical efficacy and manageable toxicity in relapsed/refractory BRAF V600-mutant pediatric LCH, with most responses ongoing. Safety was consistent with that reported in other pediatric and adult conditions treated with dabrafenib plus trametinib.

P2, N=165, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting

P2, N=35, Recruiting, Anita Turk | Trial completion date: Sep 2023 --> Jul 2024 | Trial primary completion date: Jun 2023 --> Jun 2024

In addition, we found that enhanced phosphorylation of proteins, including Tank-binding kinase 1 (TBK1), as well as high expression of B cell lymphoma 2 (Bcl-2), correlated with low sensitivity to MEK inhibitors. Taken together, this study shows that mutational status and signaling protein profiling might be used in further studies to predict drug sensitivities and identify resistance markers in MM.

The combination of C + V has antitumor activity in heavily pretreated patients with CRC with BRAF mutations.

Cobimetinib plus Dexamethasone were administered for two 28-day cycles followed by the addition of an Ixazomib, Pomalidomide and Dexamethasone (IPd) backbone therapy for all subsequent treatment cycles until disease progression. After exposure to Cobimetinib, the plasma cell clusters that expressed higher levels of this MAPK signature decreased in proportion relative to clusters with lower expression of MAPK. In summary, here we report on our initial observations of dynamic transcriptional changes in specific immune and myeloma cell compartments that are associated with targeting the MAPK pathway in the MyDrug C1 sub-protocol.

Approximately 25% of MTC tumors lack activating point mutations in RET or RAS genes. Analysis of actionable fusion mutations should be considered if there is metastatic disease. High serum calcitonin levels are not pathognomonic for MTC and tumor histology may overlap with neuroendocrine lung cancers, creating a diagnostic challenge.

P2, N=165, Not yet recruiting, National Cancer Institute (NCI)

According to our findings, KIF22 is highly expressed in pancreatic cancer and demonstrates a poor clinical prognosis. It regulates the cell cycle via the MEK/ERK/P21 signaling axis and promotes the development of pancreatic cancer.

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.

P2, N=35, Recruiting, Anita Turk | Trial completion date: Sep 2022 --> Sep 2023 | Trial primary completion date: Jun 2022 --> Jun 2023

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.

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.

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.

P1b, N=150, Recruiting, Memorial Sloan Kettering Cancer Center

P2, N=35, Recruiting, Anita Turk | Trial primary completion date: Sep 2021 --> Jun 2022

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.

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.

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.

Molecular profiling demonstrated high tumour mutational burden and EGFR/MAPK pathway activation as novel therapeutic targets in mEPC.