Mentor: Gopal Ramachandran, Chemical Biology
Lung cancer has emerged as the leading cause of cancer death in the world. Non-small cell lung cancer (NSCLC) accounts for 75-80% of all lung cancers. Over 90% of NSCLC contain mutations in EGFR, BRAF and K-Ras. Although there is treatment for a subset of NSCLC patients with EGFR mutations, treatment for patients with BRAF mutations or K-Ras mutations remains an unmet medical need and thus provides the motivation for this project.
We used high throughput small molecule screens in an attempt to find genotype- specific inhibitors for K-Ras mutants. As measured by IC_50 values, our experiments yielded three compounds which displayed potential genotype-specific inhibition of K-Ras mutants. At best, we observed nearly a 10-fold difference in sensitivity when comparing compound IC_50 values in K-Ras mutants to those in EGFR and BRAF mutants. Although all three compounds of interest belong to HDAC-biased libraries, the mechanism governing the observed specificity remains to be elucidated. These molecules are lead compounds that may require further chemical modifications to enhance their biological specificity. This project aims to identify starting points for molecularly-targeted cancer therapeutics.
"My summer research experience at the Broad was truly transformative! My research project allowed me to investigate a scientific issue that is very near and dear to my personal passions and scientific curiosity. I came to lab everyday eager to perform scientific procedures which may revolutionize modern cancer therapeutics and biomedical research.
The Broad has the opportunity to completely transform medicine by using interdisciplinary science with a genomic-based approach."
Flavian Brown, a biology senior at Carleton College, used high throughput small molecule screens in an attempt to find genotype specific inhibitors for K-Ras mutants.