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

Abstract

<div>AbstractPurpose:<p>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.</p>Experimental Design:<p>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.</p>Results:<p>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.</p>Conclusions:<p><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.</p></div>