Focal Adhesion Kinase Provides a Collateral Vulnerability That Can Be Leveraged to Improve mTORC1 Inhibitor Efficacy

SIMPLE SUMMARY: While the PI3K/AKT/mTORC1 pathway is highly active in breast cancer, mTORC1-targeting drugs are not effective in all breast cancer subtypes. To identify potential resistance mechanisms, we utilized a mouse model of breast cancer that continues to grow in the presence of the mTORC1 inhibitor, rapamycin. This treatment caused changes in the activity of genes that control the environment surrounding the tumor cells (the extracellular matrix or ECM). To determine if the ECM can modulate mTORC1 inhibitor effectiveness, we targeted focal adhesion kinase (FAK), an integral protein that mediates signaling from the ECM into the cell. In models that are relatively resistant to mTORC1 inhibitors, blocking FAK improved the ability of mTORC1 inhibitors to suppress tumor growth. However, in models that are sensitive to mTORC1 inhibitors, FAK suppression had no effect. These results provide preclinical evidence that the dual targeting of FAK and mTORC1 may improve therapeutic impact in cancers that are resistant to mTORC1 inhibitors. ABSTRACT: The PI3K/AKT/mTORC1 pathway is a major therapeutic target for many cancers, particularly breast cancer. Everolimus is an mTORC1 inhibitor used in metastatic estrogen receptor-positive (ER+) and epidermal growth factor receptor 2-negative (HER2-) breast cancer. However, mTORC1 inhibitors have limited efficacy in other breast cancer subtypes. We sought to discover collateral sensitivities to mTORC1 inhibition that could be exploited to improve therapeutic response. Using a mouse model of breast cancer that is intrinsically resistant to mTORC1 inhibition, we found that rapamycin alters the expression of numerous extracellular matrix genes, suggesting a potential role for integrins/FAK in controlling mTORC1-inhibitor efficacy. FAK activation was also inversely correlated with rapamycin response in breast cancer cell lines. Supporting its potential utility in patients, FAK activation was observed in >50% of human breast cancers. While blocking FAK in mouse models of breast cancer that are highly responsive to rapamycin had no impact on tumor growth, FAK inhibition sensitized rapamycin-resistant tumors to mTORC1 inhibition. These data reveal an innate dependency on FAK when mTORC1 signaling is lost in tumors that are resistant to mTORC1 inhibitors. They also suggest a precision medicine approach to improving mTORC1 inhibitor efficacy in resistant cancers by suppressing FAK signaling.