Project 1: Understanding the role of cell death in KRAS-mutant clonal bias in non-small cell lung cancer (NSCLC)

Coworkers: Josefina Stanka

Although almost all KRAS mutations found in clinical NSCLC samples are activating mutations in amino acid positions G12, G13 or Q61, there is a strong bias for which amino acid exchange mutation is found most frequently. In NSCLC, G12C is found at the highest frequency (about 36% of all KRAS-mutated cases) whereas G13C, an almost identical mutation is only found with a rate of about 3%. Interestingly, most point mutant variants do not significantly differ in their activity which thus cannot account for their different frequencies seen in patients. In order to investigate the hypothesis that differential cell death selection might account for this bias, we are making use of human and murine cell line systems with inducible KRAS knockout (A and B) and reconstitution to identify molecular mechanisms responsible for this skewed rate. This project is funded through the Max-Eder Programme of the Deutsche Krebshilfe.