Defining Determinants of the Lineage Identity Program in Lung Cancer and Therapeutic Resistance

Lillian Eichner, PhD, is assistant professor of Biochemistry and Molecular Genetics. She received a new R01 grant from the National Cancer Institute to uncover insights into the molecular understanding of a tumor suppressor. She highlights the aims of the project, new steps and the goals of this research.

What are the aims of the project?  

The LKB1/STK11 tumor suppressor is causally inactivated in about 20 percent of Non-Small Cell Lung Cancer (NSCLC) cases, yet major attributes of LKB1 mutant tumor biology remain to be understood. Patients with LKB1 mutant lung tumors have a uniquely poor prognosis corresponding to a tremendous unmet need for effective therapeutic options. Clinically, LKB1 mutation is associated with therapeutic resistance to standard-of-care chemotherapy and immunotherapy. Furthermore, patients with co-occurring KRAS and LKB1 mutations, which comprise about 30 percent of the mutant KRAS NSCLC patient population, develop resistance to KRAS inhibitors within months of treatment. Therefore, our goal is to define the molecular mechanisms which drive KRAS, LKB1 mutant lung tumor growth and therapeutic resistance, with the ultimate goal of improving patient outcomes. However, mechanistically how LKB1 directs HDAC3 function, and how KRAS pathway inhibitors intersect with the LKB1/HDAC3 pathway, remains unclear. This project aims to define the molecular mechanisms mediating LKB1-specific control of HDAC3 function in lung cancer and therapeutic resistance.  

We have uncovered an LKB1-specific mechanism of therapeutic resistance in KRAS mutant lung tumors. We discovered that HDAC3 cooperates with the lung cancer lineage factor NKX2-1 to drive a unique transcriptional program in lung cancer cells with LKB1 mutation. We found that resistance to KRAS pathway inhibitors hyperactivates HDAC3/NKX2-1 function, and this can be reversed by co-treatment with HDAC3-targeting drugs. Importantly, LKB1 is a molecular determinant of this pathway. Leveraging molecular understanding of this vulnerability, we discovered a new combination therapy approach using existing, clinically-tolerated therapeutics which elicits therapeutic benefit in KRAS, LKB1 mutant lung tumors in vivo. We are working toward initiation of a clinical trial testing this concept, but several key mechanistic questions remain. In this project, we seek to: 

1. Determine how LKB1 regulates HDAC3 and NKX2-1 function in NSCLC cells. 
2. Test if LKB1 status dictates whether KRAS pathway inhibition and entinostat combination treatment controls lung tumor growth. 
3. Define how KRAS pathway inhibitors impact HDAC3/NKX2-1 to regulate lung tumor growth. 

What are your next steps? 

We will use genomics and transcriptomics to identify the molecular mechanisms underlying LKB1-specific regulation of HDAC3/NKX2-1 function in lung cancer cells, and how KRAS pathway inhibition impinges on this molecular program. 

We will carry out preclinical studies to determine whether tumor genetics determines this druggable dependency.  

What do you hope will come out of this funded research? 

Overall, this work will uncover important insights into the molecular understanding of the tumor suppressor function of LKB1. Distinct HDAC3/NKX2-1 activity is a feature of LKB1 mutation that remains to be completely understood or maximally exploited for therapeutic benefit. This study will elucidate how the LKB1-mutant oncogenic program dictates HDAC3/NKX2-1 function, and how KRAS pathway inhibition engages with this program. The mechanistic insights generated will pave the way toward new therapeutic approaches for treating LKB1 mutant lung cancer patients, and assess relevance for broader lung cancer indications as well. This study provides a means to an end for maximizing potential clinical benefit from targeting this therapeutically tractable pathway. 

Learn more about the project here.