Synergy of Copanlisib with Epigenetic Inhibitor in PIK3CA-Driven NSCLCs

Precision medicine opportunities for lung cancer are poised to revolutionize the treatment of this deadly disease. PIK3CA, the gene that encode P110á a subunit of the PI3K intracellular signaling kinase involved in signaling growth and survival for cancer cells, is activated in 40% of non-small cell lung cancers by both mutation and genomic amplification. Many PI3K inhibitors have been developed, but these drugs have failed to reduce PIK3CA-mutant lung cancers in clinical trials. My laboratory’s preliminary data suggest that inhibition of the epigenetic enzyme EZH2 represents a precision medicine opportunity for patients with PIK3CA-driven lung tumors. The aims proposed here test this clinically promising drug/genotype interaction both in vivo and in vitro. I propose to build a panel of human isogeneic models in which the only difference is the presence or absence of mutant or amplified PIK3CA. Using these lines, I will explore the effects of EZH2 inhibition on cell growth and survival in vitro and in vivo. I will examine combining EZH2 inhibition with the PIK3CA inhibitors still in clinical trials. I will also develop a new mouse model of lung cancer with the most common PIK3CA mutation, E545K, to interrogate this drug/genotype interaction in the pre-clinical setting. If the Aims are successful, future studies will focus on discovering the molecular mechanism through which EZH2 inhibition kills PIK3CA driven tumor cells and may lead to clinical trials for lung cancer patients.