Targeting the CDK4/6-Rb Pathway Enhances Response to PI3K Inhibition in <i>PIK3CA</i>-Mutant Lung Squamous Cell Carcinoma.

Abstract

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. PI3K inhibitors alone and in combination with CDK4/6 inhibitors were evaluated in previously established LUSC patient-derived xenografts (PDX) using an <i>in vivo</i> screening method. Screening results were validated with <i>in vivo</i> expansion to 5 to 8 mice per arm. Pharmacodynamics studies were performed to confirm targeted inhibition of compounds. Consistent with results from The Cancer Genome Atlas analysis of LUSC, genomic profiling of our large cohort of LUSC PDX models identified PI3K pathway alterations in over 50% of the models. <i>In vivo</i> screening using PI3K inhibitors in 12 of these models identified <i>PIK3CA</i> mutation as a predictive biomarker of response (<20% tumor growth compared with baseline/vehicle). Combined inhibition of PI3K and CDK4/6 in models with <i>PIK3CA</i> mutation resulted in greater antitumor effects compared with either monotherapy alone. In addition, the combination of the two drugs achieved targeted inhibition of the PI3K and cell-cycle pathways. <i>PIK3CA</i> 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 <i>PIK3CA</i>-mutant LUSC.