Targeting KRASG12V Mutant Cancers: Profound Anti-Tumor Activity of Novel Tri-Complex Inhibitors in Preclinical Studies

The KRAS G12V mutation is a major medical challenge, with approximately 44,000 new cases in the US each year. It is prevalent in various cancers, including non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic cancer, with occurrence rates of 6%, 10%, and 26% respectively. RAS proteins, when bound to GTP, promote cell growth and survival. However, the KRAS G12V mutation results in a protein that is mostly in the GTP-bound state, causing excessive signaling through RAF and other effectors. This mutation has a lower GTP hydrolysis rate compared to other KRAS variants, making it crucial to target this state for effective treatment. No direct inhibitors for this specific state have been reported.

Our research has developed a series of small molecule inhibitors aimed at multiple oncogenic RAS in the GTP-bound state. We present the preclinical findings of KRAS G12V inhibitors that form a tri-complex with cyclophilin A (CypA) and the active GTP-bound form of KRAS G12V. These inhibitors rapidly disrupt the interaction between RAS and its effectors in cancer cells with the KRAS G12V mutation, reducing RAS pathway signaling, inhibiting growth, and inducing cell death.

In vivo studies show that these inhibitors lead to significant and sustained suppression of tumor RAS pathway activation after oral administration. They also exhibit a prolonged pharmacodynamic effect in tumors, possibly due to high affinity binding to CypA and retention in tumor tissue. In xenograft models of NSCLC, CRC, and pancreatic cancers with the KRAS G12V mutation, the inhibitors are well-tolerated and result in significant tumor regressions, with complete responses observed in some cases.

Additionally, these inhibitors reduce the expression of immune checkpoint proteins PD-L1 and CD73 on cancer cells, which could enhance the immune response against tumors. The targeting of the GTP-bound form of KRAS G12V opens up various combination therapy opportunities, especially in cancers where single-agent treatment may not be sufficient. This could include therapies targeting upstream and downstream nodes of the RAS pathway, as well as parallel pathways.

The tri-complex inhibitors targeting the active state of KRAS G12V are expected to counteract resistance mechanisms in cancers that rely heavily on RAS, offering a promising therapeutic strategy for treating cancers with a high unmet medical need.