Defining determinants of the lineage identity program in lung cancer and therapeutic resistance

About This Grant

PROJECT SUMMARY/ABSTRACT Recent advances have uncovered important mechanistic insights regarding how LKB1/STK11 functions as a tumor suppressor in the lung, yet understanding of LKB1 mutant lung tumor biology, and how to successfully treat this devastating disease, remains incomplete. Our cancer biology studies have revealed that HDAC3 is essential for LKB1 mutant lung tumor growth, and that HDAC3 is a druggable vulnerability in therapeutic resistance to KRAS pathway inhibitors. However, a knowledge gap remains in our mechanistic understanding of how LKB1 loss regulates HDAC3/NKX2-1 complex function in lung tumors, and how KRAS pathway inhibitors impinge on this molecular node. Our proposal aims to bridge this knowledge gap by (1) determining how LKB1 specifies the HDAC3/NKX2-1 program in lung cancer cells, (2) testing if LKB1 status dictates whether KRAS pathway inhibition and entinostat combination treatment controls lung tumor growth, and (3) defining how KRAS pathway inhibitors impact HDAC3/NKX2-1 to regulate lung tumor growth. We will use genomics and mass spectrometry approaches coupled with lung cancer cell lines and mouse models of lung cancer to achieve these goals. The use of mouse models for a limited set of experiments is necessary in order to accurately understand the LKB1 pathway, as this pathway is established to function differently in vitro compared to in vivo. Moreover, mice are essential for understanding the impact on tumor growth control in the context of an intact immune system. Overall, these studies will advance our understanding of the genetic and therapeutic mechanisms modulating HDAC3 complex function in lung tumor biology, and pave the way toward improved therapeutic options for patients with LKB1 mutant lung cancer.