• Dual RAF/MEK inhibitor VS-6766 for treatment of KRAS mutant NSCLC: novel combinations targeting G12C or G12V variants

      Coma, S.; Chowdhury, S.; Musteanu, M.; Stewart, A.; Pickard, L.; Krebs, Matthew G; Minchom, A.; Banerji, U.; Barbacid, M.; Pachter, J.; et al. (2021)
      Introduction:KRAS is mutated in 25% of non-small cell lung cancer(NSCLC) adenocarcinoma, with KRAS G12C and G12V mutationsoccurring inw13% andw7% of patients, respectively. Whereas G12Cinhibitors (G12Ci) sotorasib (AMG 510) and adagrasib (MRTX849) havedemonstrated promising antitumor activity in patients with KRAS G12Cmutant (mt) NSCLC, KRAS G12V mt NSCLC remains an unmet need. VS-6766 is a unique dual RAF/MEK inhibitor which has shown singleagent activity against KRAS G12V mt NSCLC (Guo Lancet Oncology2020).Methods:We assessed synergistic antitumor effects of VS-6766with G12C or focal adhesion kinase (FAK) inhibitors in KRAS G12C orG12V NSCLC preclinical models, respectively.Results:In KRAS G12Cmt NSCLC, emerging data suggest that G12Ci monotherapy may beinsufficient for maximal depth or duration of response, and combina-tions with agents that target additional nodes in the RAS pathway(vertical blockade) may be necessary. In 3D proliferation assays, VS-6766 was synergistic with both sotorasib and adagrasib in reducingviability of a panel of KRAS G12C mt NSCLC cell lines. Accordingly, VS-6766 effectively suppressed pERK across KRAS G12C mt NSCLC celllines as a single agent, and the combination of VS-6766 + G12Ci showedimproved depth and duration of inhibition relative to G12Ci alone. InKRAS G12C mt NSCLC xenograft models (H2122, H358), combinationwith VS-6766 (0.3 mg/kg QD) augmented tumor growth inhibition bysotorasib, whereas trametinib (0.3 mg/kg QD) was much less effectivein augmenting sotorasib efficacy. Strikingly, triple combination of VS-6766, sotorasib and FAK inhibitor conferred tumor reductions of 35% in all mice in both models. In KRAS G12V mt NSCLC, CRAFsignaling was essential for tumor progression in a genetically engi-neered mouse tumor model (Sanclemente Cancer Cell 2018), providingrationale for testing the RAF/MEK inhibitor VS-6766 in KRAS G12V mtNSCLC. As RAF and MEK inhibition have been reported to activate FAKas a potential resistance mechanism, the combination of VS-6766 withthe FAK inhibitor defactinib has been studied. In 3D proliferation as-says in vitro, VS-6766 was synergistic with defactinib in reducingviability of KRAS mt cell lines with the broadest synergy observed inKRAS G12V mt cell lines, as compared with G12C and G12D cell lines. Ina KRAS G12V mt/TP53 null NSCLC model, which has previously beenshown to be CRAF dependent, VS-6766 monotherapy induced statisti-cally significant tumor regression, while trametinib at the same dosedid not. FAK inhibition further augmented the tumor regressioninduced by VS-6766. These preclinical data correlate well with theclinical observation of partial responses in patients with KRAS G12V mtNSCLC treated with VS-6766 monotherapy (Guo Lancet Oncology2020) or in combination with defactinib. Furthermore, this combina-tion regimen of VS-6766 with defactinib exhibited a manageable safetyprofile with no patients discontinuing for adverse events (Krebs AACR2021).Conclusion:These results support the ongoing registration-directed study evaluating VS-6766±defactinib for treatment ofrecurrent KRAS G12V mt NSCLC (NCT04620330) and provide rationalefor the clinical evaluation of VS-6766 in combination with a G12C in-hibitor for treatment of KRAS G12C mt NSCLC.
    • FAK inhibition alone or in combination with adjuvant therapies reduces cancer stem cell activity

      Timbrell, Simon; Aglan, Hosam; Cramer, Angela; Foden, P.; Weaver, D.; Pachter, J.; Kilgallon, Aoife; Clarke, Robert B; Farnie, Gillian; Bundred, Nigel J; et al. (2021)
      Cancer stem-like cells (CSC) contribute to therapy resistance and recurrence. Focal adhesion kinase (FAK) has a role in CSC regulation. We determined the effect of FAK inhibition on breast CSC activity alone and in combination with adjuvant therapies. FAK inhibition reduced CSC activity and self-renewal across all molecular subtypes in primary human breast cancer samples. Combined FAK and paclitaxel reduced self-renewal in triple negative cell lines. An invasive breast cancer cohort confirmed high FAK expression correlated with increased risk of recurrence and reduced survival. Co-expression of FAK and CSC markers was associated with the poorest prognosis, identifying a high-risk patient population. Combined FAK and paclitaxel treatment reduced tumour size, Ki67, ex-vivo mammospheres and ALDH+ expression in two triple negative patient derived Xenograft (PDX) models. Combined treatment reduced tumour initiation in a limiting dilution re-implantation PDX model. Combined FAK inhibition with adjuvant therapy has the potential to improve breast cancer survival.