Drug targets. - Not all BRAF mutations are equal, falling into 3 different classes based on mechanism of action and therapeutic sensitivity

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Oct. 4, 2019

SCIENTIFIC

Drug targets.


Not all BRAF mutations are equal, falling into 3 different classes based on mechanism of action and therapeutic sensitivity. Early data in colorectal cancer suggest divergent clinical features and outcomes for class 1, 2 and 3 variants.


Class 1, 2 and 3 BRAF mutated metastatic colorectal cancer: a detailed clinical, pathological and molecular characterization
American Association for Cancer Research.4-2019

Purpose BRAF mutations are grouped in activating RAS-independent signaling as monomers (class 1 - V600E) or as dimers (class 2 - codons 597/601), and RAS-dependent with impaired kinase activity (class 3 - codons 594/596). While clinical, pathological and molecular features of V600E BRAF mutated metastatic colorectal cancer (mCRC) are well known, limited data are available from the two other classes. Experimental Design Data from 117 BRAF (92 class 1, 12 class 2, and 13 class 3) mutated mCRC patients were collected. 540 BRAF wt mCRC were included as control. Immunohistochemical profiling was performed to determine the consensus molecular subtypes (CMS), cytokeratins 7/20 profiles, tumor infiltrating lymphocytes (TILs) infiltration and BM1/BM2 categorization. OS and PFS were evaluated by Kaplan-Meier and log-rank test. Results Class 3 BRAF mutated mCRC were more frequently left sided (p=0.0028), pN0 (p=0.0159), and with no peritoneal metastases (p=0.0176) compared to class 1, whereas class 2 cases were similar to class 1. HR for OS, as compared to BRAF wt, was 2.38 (95%CI 1.61-3.54) for class 1, 1.90 (95% CI 0.85-4.26) for class 2 and 0.93 (95% CI 0.51-1.69) for class 3 (p<0.0001). Class 2 and 3 tumors were all assigned to CMS2-3. A higher median CD3/CD8 positive lymphocytes infiltration was observed in BRAF mutated class 2 (p= 0.033) compared to class 3 cases. Conclusions For the first time different clinical, pathological features and outcome data are reported according to the 3 BRAF mutation classes in mCRC. Specific targeted treatment strategies should be identified in the next future for such patients.

https://clincancerres.aacrjournals.org/content/early/2019/04/09/1078-0432.CCR-19-0311


KRAS (mutated in ~15% of cancer) has long thought to be untargetable. Clinical trials of a G12C specific inhibitor, however, are showing promise. New preclinical data point to combining KRAS inhibition with blockade of MTOR and IGF1R pathways.

Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer

Science Translational Medicine  18 Sep 2019:Vol. 11, Issue 510, eaaw7999

KRAS represents an excellent therapeutic target in lung cancer, the most commonly mutated form of which can now be blocked using KRAS-G12C mutant-specific inhibitory trial drugs. Lung adenocarcinoma cells harboring KRAS mutations have been shown previously to be selectively sensitive to inhibition of mitogen-activated protein kinase kinase (MEK) and insulin-like growth factor 1 receptor (IGF1R) signaling. Here, we show that this effect is markedly enhanced by simultaneous inhibition of mammalian target of rapamycin (mTOR) while maintaining selectivity for the KRAS-mutant genotype. Combined mTOR, IGF1R, and MEK inhibition inhibits the principal signaling pathways required for the survival of KRAS-mutant cells and produces marked tumor regression in three different KRAS-driven lung cancer mouse models. Replacing the MEK inhibitor with the mutant-specific KRAS-G12C inhibitor ARS-1620 in these combinations is associated with greater efficacy, specificity, and tolerability. Adding mTOR and IGF1R inhibitors to ARS-1620 greatly improves its effectiveness on KRAS-G12C mutant lung cancer cells in vitro and in mouse models. This provides a rationale for the design of combination treatments to enhance the impact of the KRAS-G12C inhibitors, which are now entering clinical trials.

https://stm.sciencemag.org/content/11/510/eaaw7999

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