Unraveling novel targets for lung adenocarcinomas drivers’ mutations with poor prognosis and poor response to immune checkpoint inhibition

Aim/goals:

1. Sequence early-stage lung adenocarcinoma (LADC) patient’s tumors with MET exon 14 skipping mutations that have poor prognosis as well as LADC tumors with poor response to immune checkpoint inhibition (ICI), namely KRAS+KEAP1 co-occurring mutations and KRAS+STK11 co-occurring mutation.
2. Test drug combinations inferred from sequencing data on patient-derived organoids and xenografts from those tumors.
3. Devise new therapeutic targets that could be tested in subsequent clinical trials.

 

Summary:

Lung cancer is the primary cause of cancer-related death around the world, accounting for over 28% of cancer-related mortality, more than breast, colon, prostate, and pancreas combined. While local treatments for non-small cell lung carcinoma (NSCLC; 85% of all forms of lung cancers) are frequently effective, a high proportion of patients with potentially “curable disease” recur locally and/or distantly, and it is this metastatic progression that leads to death. Although MET alterations are found in only ~3-4% of LADC patients, MET exon 14 skipping driver mutations are associated with poor prognosis in NSCLC. Despite the success of ICI in LADCC and the development of MET targeted therapies, acquired resistance and lack of response to treatment is way too common for this cohort of patients. Thus, there is an unmet need to develop novel targets and treatment strategies.

Indeed, ICI has shown tremendous benefit for early-stage NSCLC patients; however, 30-50% of patients still do not respond to treatment. Amongst those are patients with tumors harboring KRAS and KEAP1 co-occurring mutations as well as KRAS and STK11 co-occurring mutations. KRAS being the most mutated driver mutation in LADC (~40% of all LADC), and KRAS being still undruggable (with the exception of KRAS G12C), there is again a huge opportunity to improve ICI response for this cohort of patients.

We propose to sequence treatment naïve MET and KRAS mutant NSCLC tumors to unravel novel targetable biomarkers and to test drug combinations (salvage therapies) inferred from the sequencing data on patient-derived organoids and xenografts from those patients. By correlating sequencing data with mutational signature, we will devise new therapeutic targets that could be tested in subsequent clinical trials. This will provide novel targeted therapies for this NSCLC patient population.