Lung cancer (NSCLC) remains the leading cause of cancer deaths globally, despite significant advances, including the use of immune checkpoint inhibitor (ICI) therapies. KRAS inhibitors are a new class of drugs, increasingly important in multiple tumor types, including colorectal, pancreatic and NSCLC. KRAS mutations are present in ~30% of NSCLC, with ~40% being G12C mutations, which alone comprise 23,500 U.S. patients annually. Drugs targeting the G12C mutation have shown impressive clinical activity in previously treated patients, producing response rates of ~40%. However, the currently approved G12C inhibitors have a short duration of response (~5-6 months) due to acquisition of resistance...

Read More

Lung cancer (NSCLC) remains the leading cause of cancer deaths globally, despite significant advances, including the use of immune checkpoint inhibitor (ICI) therapies. KRAS inhibitors are a new class of drugs, increasingly important in multiple tumor types, including colorectal, pancreatic and NSCLC. KRAS mutations are present in ~30% of NSCLC, with ~40% being G12C mutations, which alone comprise 23,500 U.S. patients annually. Drugs targeting the G12C mutation have shown impressive clinical activity in previously treated patients, producing response rates of ~40%. However, the currently approved G12C inhibitors have a short duration of response (~5-6 months) due to acquisition of resistance. The mechanisms driving acquired resistance are not fully defined for these approved drugs. Additionally, it is unknown if other KRAS inhibitors in development will have similar or distinct adaptive resistance mechanisms. Given the current use of immune checkpoint inhibitor (ICI) therapies in NSCL and their potential for durable long-term responses, KRAS inhibitor combinations with ICI therapy may be the best overall strategy, if combinations can be developed. Therefore, there is a critical unmet need for research to understand the mechanisms of adaptive resistance to the various KRAS inhibitors and development of combination strategies to prevent the emergence or reverse resistance. Preliminary work by our broad multidisciplinary team found that resistance to KRAS inhibitors emerged in concert with activation of multiple tumor cell pathways. We also observed a profound alteration in the tumor immune composition, suggesting that KRAS inhibitor resistance reprograms the tumor cells to actively suppress an anti-tumor immune response. We will use preclinical murine and human models, and deep analysis of patient tumor biopsies to determine the role of the identified pathways in treatment resistance, immune suppression, and test if combination therapies can reverse the resistance.

Read Less