15 Identification of new combination therapies for lung cancer tumours harbouring kras mutations

Introduction Oncogenic mutations in KRAS are frequent in non-small cell lung cancer (NSCLC) and have been associated with poor prognosis and resistance to existing therapies. We have previously shown that NSCLC cells harbouring KRAS mutations are more sensitive than their wild-type counterparts to inhibition of KRAS downstream effectors MEK and RAF and to treatment with IGF1R inhibitors. Material and methods In order to identify complementary targets for the improvement of IGF1R and/or MEK targeting therapies, we performed a whole-genome shRNA screen with KRAS-mutant NSCLC cells. Validation was performed using shRNAs and small molecule inhibitors in a panel of NSCLC cell lines. In vivo efficacy of drug combinations was measured in mouse models of Kras-induced NSCLC using CT scanning. Results and discussions The list of sensitizers to IGF1R inhibitors included several genes encoding components of the mTOR pathway. Viability assays in a panel of lung cancer cell lines confirmed that combining IGF1R inhibitors with mTOR inhibitors, both rapalogs and kinase inhibitors, resulted in a synergistic anti-proliferative effect in KRAS-mutant NSCLC cells. Mechanistic investigations demonstrated that IGF1R inhibitors blocked reactivation of the PI3K pathway induced by mTOR inhibition, resulting in a robust suppression of PI3K and mTORC1 signalling. Addition of a MEK inhibitor to the combination produced a more profound and durable suppression of cell proliferation and a stronger induction of apoptosis by inhibiting the main downstream pathways controlled by KRAS. Notably, the inhibition of these signalling pathways was stronger in KRAS-mutant cells than in wild-type cells. In order to achieve strong downstream pathway inhibition even more specifically in KRAS-mutant cells, we used the KRAS-G12C mutant inhibitor, ARS-1620. Interestingly, addition of mTOR and IGF1R inhibitors vastly increases effectiveness of the KRAS-G12C inhibitor. Finally, we validated the drug combinations in mouse models of KRAS-induced NSCLC. Results showed that combined mTOR, IGF1R and MEK inhibition produced a marked tumour regression in a NSCLC mouse model driven by mutant Kras and p53 loss-of-function and also in urethane-induced lung tumours. Conclusion We have demonstrated that a profound inhibition of the main pathways downstream KRAS is needed to achieve a durable suppression of cell viability in NSCLC cells harbouring KRAS mutations. These findings suggest potential novel therapeutic strategies for KRAS mutant NSCLC tumours.