The cytotoxicity of trametinib (MEK inhibitor), DT2216 (BCL-xL degrader) and afatinib (pan-EGFR inhibitor) and their combination was tested in patient-derived, primary PDAC cells using a live cell imaging system. Pathway analysis revealed the addition of afatinib in triplet regimen further inhibited PI3K/AKT effectors of p90RSK, p70S6K, and GSK3α/β along with a secondary pathway of P38 MAPK. Our study identifies an important contribution of EGFR inhibition to elevate the response of PDAC, supporting a clinical assessment of this triplet combination in patients.

In addition, the high expression of model gene produced drug resistance to trametinib, selumetinib and RDEA119 (refametinib). The prognostic risk model based on six prognostic related DEGs is an independent prognostic factor of HCC, which can effectively predict the survival and prognosis of HCC patients.

In ReNeu, the largest multicenter NF1-PN trial reported to date, mirdametinib treatment demonstrated significant confirmed ORRs by BICR, deep and durable PN volume reductions, and early, sustained, and clinically meaningful improvement in pain and HRQOL. Mirdametinib was well-tolerated in adults and children.

P1/2, N=75, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

Interestingly, C2 was less effective in suppressing A375 and B16-F10 cell lines (LD50 C2 < LD50 Dabrafenib/control), with its LD50 value nearly matching that of the Trametinib control in B16-F10 cell lines. Consequently, GSCRE, especially C2 or Caulersin, shows promise as a new molecule for developing functional foods to combat aging and human melanoma. However, further in vivo studies and clinical trials are necessary to confirm these findings.

In addition, a PDX model with acquired resistance to osimertinib was induced, and the overactivation of RAS mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK) signaling pathway caused by the dual-specificity phosphatase 6 (DUSP6) M62I mutation was found to play a key role in the development of osimertinib resistance. Trametinib, a specific inhibitor of the MAPK-ERK pathway significantly slowed down the tumor growth in osimertinib-resistant PDX models, providing an alternative treatment in patients after osimertinib failure.

Dabrafenib plus trametinib, as the first tumor-agnostic therapy, has been approved by the US Food and Drug Administration for the treatment of adult and pediatric patients aged 6 years and older harboring a BRAF V600E mutation with unresectable or metastatic solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options. Therefore, we have established a universal and systematic strategy for diagnosing and treating solid tumors with BRAF mutations. In this expert consensus, we (1) summarize the epidemiology and clinical characteristics of BRAF mutations in different solid tumors, (2) provide recommendations for the selection of genetic testing methods and platforms, and (3) establish a universal strategy for the diagnosis and treatment of patients with solid tumors harboring BRAF mutations.

The combined application of ERK inhibitors, U0126 or trametinib, with the VEGFR inhibitor Apatinib, additively suppresses angiogenesis and tumor growth of HCC1806 in nude mice. These findings provide new therapeutic strategies for TNBC.

P1, N=124, Recruiting, Pfizer | Trial completion date: Sep 2028 --> Aug 2029 | Trial primary completion date: Mar 2027 --> Feb 2028

P1, N=46, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Nov 2024 --> Nov 2025

P2, N=40, Recruiting, Memorial Sloan Kettering Cancer Center | N=20 --> 40

P2, N=15, Recruiting, Verastem, Inc.

P1, N=14, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Recruiting --> Active, not recruiting

P1/2, N=27, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2024 --> Oct 2025

P1/2, N=85, Active, not recruiting, Verastem, Inc. | Recruiting --> Active, not recruiting | Trial primary completion date: Jul 2024 --> Dec 2024

The tumor growth inhibitory rate was 99.36% for dabrafenib, trametinib, and osimertinib; 99.25% for osimertinib plus vemurafenib; 98.92% for osimertinib, encorafenib, and cetuximab; and 62.83% for pemetrexed plus carboplatin. NGS analysis identified major resistance mechanisms following the triple-targeted therapy, including the EGFR-dependent pathway, EGFR and BRAF V600E-dependent pathway, and an off-target mechanism. EGFR/BRAF/MEK triple-targeted therapy is an effective and safe approach for treating EGFR-mutated NSCLC patients resistant to EGFR-TKIs with acquired BRAF V600E mutations.

P2, N=24, Active, not recruiting, Providence Health & Services | Recruiting --> Active, not recruiting | N=40 --> 24

Additionally, the transcriptomes of these cells were reprogrammed to become highly responsive to chemotherapy (cisplatin), targeted therapy (trametinib), and epigenetic therapy (vorinostat). SCARA5 and AOX1 DNA promoters were hypermethylated in NSCLC, and SCARA5 methylation was identified as an epigenetic biomarker in tumors and liquid biopsies from NSCLC patients. Thus, we demonstrate that co-targeting G9a/DNMT1 is a promising strategy to enhance the efficacy of cancer drugs, and SCARA5 methylation could serve as a non-invasive biomarker to monitor tumor progression.

MEK inhibition with avutometinib abrogates the adaptive rebound in ERK signaling, but the antitumor effects are limited...In contrast to the NF1-deficient setting, concurrent SOS1 and SOS2 depletion is required to completely inhibit RAS signaling in NF1 wild-type cells. In sum, our data provide a mechanistic rationale for enhancing the therapeutic efficacy of MEK inhibitors by exploiting the lower residual SOS activity in NF1-null tumor cells.

P2, N=20, Terminated, University of Zurich | Recruiting --> Terminated; too few patients could be included

In terms of drug sensitivity, the high-risk group was more sensitive to vinblastine, Acetalax, VX-11e, and PD-0325901, while the low-risk group was more sensitive to Sabutoclax, SB-505124, cisplatin, and erlotinib. The prognostic risk model of ovarian cancer associated to mitochondrial genes built on the basis of public database better evaluated the prognosis of ovarian cancer patients and guided individual treatment.

P2, N=4, Terminated, M.D. Anderson Cancer Center | Completed --> Terminated; Study stopped due to slow enrollment

P2, N=10, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Oct 2025

P1/2, N=50, Not yet recruiting, C17 Council

P1, N=32, Terminated, Merck Sharp & Dohme LLC | Phase classification: P1b --> P1 | Completed --> Terminated; Business Reasons

P1/2, N=23, Active, not recruiting, SpringWorks Therapeutics, Inc. | Recruiting --> Active, not recruiting | N=136 --> 23

P1, N=105, Recruiting, BeiGene | Phase classification: P1b --> P1

No abstract available

Concomitant inhibition of both FAK (with VS-4718) and rapidly accelerated fibrosarcoma and MAPK kinase (RAF-MEK) (with avutometinib) induced tumor growth inhibition and increased survival across multiple PDAC mouse models. Combination of FAK and RAF-MEK inhibition alone improved antitumor immunity and priming of T cell responses in response to chemotherapy. These findings provided the rationale for an ongoing clinical trial evaluating the efficacy of avutometinib and defactinib in combination with gemcitabine and nab-paclitaxel in patients with PDAC and may suggest further paths for combined stromal and tumor-targeting therapies.

P3, N=921, Completed, Pfizer | Active, not recruiting --> Completed

P2, N=21, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Sep 2025

In summary, our research unveil the critical role of the MAPK-c-Fos-JunB axis in driving CAR-T cell exhaustion and terminal differentiation. These mechanistic insights significantly broaden the potential application of MEKIs to enhance the effectiveness of CAR-T therapy.

P2, N=12, Recruiting, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University

The STARBOARD SLI showed that safety across the cohorts was generally comparable to the known safety profile of each agent. The standard dose regimen of COMBO450 plus pembrolizumab was chosen as the RP3D.

Using patient tumor tissue before and after BRAFi+MEKi, two novel syngeneic murine models of BRAF V600E HGG, and patient-derived cell lines, we examined the effects of clinically relevant BRAFi+MEKi with dabrafenib and trametinib on tumor growth, cell states, and tumor-infiltrating T cells. The quadruple treatment overcame BRAFi+MEKi resistance by invigorating T cell-mediated anti-tumor immunity in murine BRAF V600E HGG. PD-L1 expression was elevated in human BRAF-mutant versus BRAF-wildtype glioblastoma clinical specimen, complementing experimental findings and suggesting translational relevance for patient care.

P2, N=98, Active, not recruiting, Pfizer | Trial completion date: Dec 2024 --> Oct 2025

Importantly, loss of wild-type Kras sensitized Kras mutant tumors to MEK1/2 inhibition though tumors eventually became resistant and then rapidly progressed. This study demonstrates the repressive role of wild-type KRAS during pancreatic tumorigenesis and highlights the critical impact of the presence of wild-type KRAS in both tumor progression and therapeutic response in pancreatic cancer.

P1, N=22, Terminated, National Cancer Institute (NCI) | Active, not recruiting --> Terminated; Drug supply issues

P4, N=166, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting | N=250 --> 166

P2, N=119, Recruiting, Intergroupe Francophone de Cancerologie Thoracique | Trial primary completion date: Sep 2024 --> Dec 2024

Two patients with BRAFv600E-mutated/CDKN2A deleted PXA-2, had progression following resection, and experienced stable/partial response at 9 months of dabrafenib use...Two patients who stopped trametinib due to side effects (significant acneiform rash/paronychia and intracranial bleeding) did not experience progression. Our experience with BRAF/MEK inhibitors' use was positive achieving response in all LGGs and provided sustained response with good quality of life for patients with HGG. Cost effectiveness analyses and patients' satisfaction comparisons with chemotherapy are needed to evaluate the routine use of these drugs in LMICs.

The BRAF V600E mutation has been identified in a subset of malignant GT, highlighting a promising therapeutic target. Here, we report the impressive clinical and morpho-metabolic response of a metastatic BRAF V600E-mutated glomangiosarcoma after treatment with encorafenib and binimetinib.