Dr. Ferdinandos Skoulidis
The University of Texas MD Anderson Cancer Center
Department of Thoracic/Head and Neck Medical Oncology
Activating mutations in the KRAS oncogene represent the most prevalent genetic driver event in lung adenocarcinoma (LUAC) (25-30%), yet, to date, strategies aimed at targeting KRAS-mutant tumors have been employed with only limited success. The considerable molecular heterogeneity of KRAS-mutant LUAC constitutes a major impediment towards this goal. We recently identified three major subsets of KRAS-mutant LUAC, defined by co-occurring genomic alterations in STK11/LKB1 (the KL subgroup), TP53 (KP) and CDKN2A/B, coupled with low expression of the TTF1 transcription factor (KC). Importantly, the three subgroups exhibited distinct biology, immune profiles and therapeutic vulnerabilities (Skoulidis F. et al., Cancer Discovery, 2015).Thus, co-mutations represent major determinants of signaling diversification downstream of mutant KRAS and can impact cell-autonomous cancer hallmarks as well as influence the reciprocal relationships between tumor cells and their microenvironment, including their interplay with the immune system. Nonetheless, a systematic exploration of the impact of co-mutations on facets of KRAS-mediated lung carcinogenesis and the response of KRAS-mutant tumors to therapy is currently lacking. Work in my laboratory has three overarching aims:
- To systematically dissect the role of co-occurring genetic events on the biology, heterotypic (micro-environmental) interactions and therapeutic responsiveness of KRAS-mutant LUAC.
- To develop rational therapeutic approaches for the three major subsets of KRAS-mutant LUAC, defined on the basis of co-occurring genetic events in STK11/LKB1 (KL), TP53 (KP) and CDKN2A/B (KC).
- To model the impact of endogenous genomic instability mechanisms on the evolution, heterogeneity, immunogenicity and therapeutic response of KRAS-mutant LUAC to targeted therapy and immunotherapy.
Our experimental approach integrates multi-platform, bio-informatic analyses of in house and publicly available datasets of human LUAC with development of novel genetically engineered murine models (GEMMs) of Kras-mutant lung cancer and high throughput functional genetic screens that utilize state of the art genome editing tools. Our focus is on adopting a rigorous scientific approach to answer clinically relevant biological questions, with a declared ambition to rapidly translate our findings for the benefit of lung cancer patients.