BCL-2 family inhibition enhances MTORC1/2 inhibition in PIK3CA mutant colorectal cancer

Targeting PIK3CA mutant colorectal cancers (CRCs) with precision medicine strategies is of great clinical interest. However, resistance to single agent PI3K pathway inhibitors has been observed across multiple clinical trials, necessitating identification of combination therapies that overcome or prevent resistance to precision medicine strategies. Previously, our group identified that inhibition of MTORC1/2 is necessary to induce a response in PIK3CA mutant CRCs. The PI3K/MTORC1/2 inhibitor copanlisib has demonstrated some clinical activity in PIK3CA mutant solid tumors as part of the NCI MATCH trial. Here we evaluate potential combination therapies that could enhance the efficacy of copanlisib and other similar inhibitors in PIK3CA mutant CRCs. Using a novel high-throughput drug screen method in Apc and Pik3ca mutant mouse-derived cancer organoids, we identify navitoclax, a BCL-2 family inhibitor, as a drug that could potentially enhance the response to copanlisib. Across multiple in vitro and in vivo CRC models, navitoclax enhanced PI3K/MTOR inhibition (copanlisib, sapanisertib, and dactolisib) and induced apoptosis. Furthermore, we examine these combination therapies across a panel of patient-derived cancer organoids with a range of mutation profiles. These studies indicate that KRAS mutations could confer resistance. Furthermore, we identify BCL-xL as the major BCL-2 family target important for the response to this combination in this setting. This provides a strong rationale for MTORC1/2 and BCL-2 family inhibition as a potential treatment strategy for PIK3CA mutant CRCs.