EGFR amplification and PI3K pathway mutations identify a subset of breast cancers that synergistically respond to EGFR and PI3K inhibition

Abstract

EGFR family receptor tyrosine kinase signaling is commonly dysregulated in cancer by amplification or activating mutations. Although studies have investigated dual EGFR/PI3K inhibition in breast cancer, they have not determined biomarkers which predict success. We present evidence of a patient subset with EGFR amplification and PI3Kinase pathway mutations in breast cancer which can be synergistically targeted by dual EGFR/PI3K inhibition. This study identified that EGFR amplification occurs in approximately 1-5% of breast cancer patients with shorter overall survival compared to unamplified patients. Up to 71% of EGFR amplified tumors have activating mutations in the PI3K pathway. Dual EGFR/PI3K inhibition more dramatically reduced mTOR and AKT signaling in BT20 and MDA-MB-468 cells which both have EGFR amplification and PI3K pathway activating mutations, compared to control cells. Dual inhibition synergistically reduced cell viability and increased apoptosis in MDA-MB-468 and BT20 compared to control. Single agent therapy in a BT20 xenograft model reduced tumor volume, however only the combination statistically significantly reduced tumor volume compared to control. We conclude that EGFR amplification with co-incident PI3K pathway mutations are driver mutations in a subset of breast cancers and present a subgroup of breast cancers that are more likely to respond to dual targeted therapy.