Targeting the CDK4/6-Rb pathway enhances response to PI3K inhibition in PIK3CA mutant lung squamous cell carcinoma

Purpose: Lung squamous cell carcinoma (LUSC) is a major subtype of non-small cell lung cancer characterized by multiple genetic alterations, particularly PI3K pathway alterations which have been identified in over 50% of LUSC cases. Despite being an attractive target, single agent PI3K inhibitors have demonstrated modest response in LUSC. Thus, novel combination therapies targeting LUSC are needed. Experimental Design: PI3K inhibitors alone and in combination with CDK4/6 inhibitors were evaluated in previously established LUSC patient-derived xenografts (PDX) using an in vivo screening method. Screening results were validated with in vivo expansion to n=5-8 mice per arm. Pharmacodynamics studies were performed to confirm targeted inhibition of compounds. Results: Consistent with results from The Cancer Genome Atlas (TCGA) analysis of LUSC, genomic profiling of our large cohort of LUSC PDX models identified PI3K pathway alterations in over 50% of the models. In vivo screening using PI3K inhibitors in 12 of these models identified PIK3CA mutation as a predictive biomarker of response (<20% tumor growth compared to baseline/vehicle). Combined inhibition of PI3K and CDK4/6 in models with PIK3CA mutation resulted in greater anti-tumor effects compared to either monotherapy alone. Additionally, the combination of the two drugs achieved targeted inhibition of the PI3K and cell cycle pathways. Conclusions: PIK3CA mutations predict response to PI3K inhibitors in LUSC. Combined PI3K and CDK4/6 inhibition enhances response to either single agents alone. Our findings provide a rationale for clinical testing of combined PI3K and CDK4/6 inhibitors in PIK3CA mutant LUSC.

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