Combination Therapies to Potentiate the Impact of KRAS-G12C Inhibitors
Oncogenic mutations in KRAS are frequent in non-small cell lung cancer and have been associated with poor prognosis. The recent development of KRAS-G12C mutant-specific inhibitors provides a great opportunity to selectively target tumours carrying KRAS-G12C mutations, which account for 14% of all lung adenocarcinomas. However, monotherapies targeting oncogenic drivers frequently result in rapid development of resistance and combination strategies are needed.
I will discuss two different approaches to develop combination therapies to enhance the effect of KRAS-G12C inhibitors. The classical approach is to target proliferative pathways driven by KRAS in order to potentiate the efficacy of KRAS inhibitors or to inhibit adaptation mechanisms. We have shown that simultaneous inhibition of mTOR and IGF1R vastly increases the effectiveness of KRAS-G12C inhibitors both in vitro and in vivo, without causing significant toxicities.
The second approach is to target the tumour microenvironment, especially those pathways driven by oncogenic KRAS that promote tumour evasion of the immune system. Using different lung cancer mouse models, we have observed that tumours harbouring KRAS mutations present an immunosuppressive tumour microenvironment. To investigate the role of oncogenic KRAS in immune suppression, we have characterised the changes produced by KRAS-G12C inhibition in the immune composition of the tumour microenvironment, using flow cytometry, RNAseq, and Imaging Mass Cytometry. We have observed that inhibition of oncogenic KRAS results in a positive repolarisation of the tumour microenvironment, which offers an excellent opportunity to combine KRAS-G12C inhibitors with drugs that target the tumour immune microenvironment.