PROJECT SUMMARY
Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. KRAS is a major
oncogenic driver of this disease and found in ~ 30% of all NSCLCs. Unfortunately, efforts to develop drugs that
target mutant KRAS proteins have largely been unsuccessful, since both single agent inhibition of effector
pathways downstream of KRAS or combinations have proven to be ineffective. Thus, developing novel
therapies for KRAS-driven NSCLC remains an area with a critical unmet need. The overarching goal of this
proposal is to dissect the mechanistic underpinning of how genetic ablation of CRAF induces regression of
KRAS-driven NSCLC. We have generated a KRAS-driven, human NSCLC cell line with inducible CRAF
expression that undergoes apoptosis upon CRAF knockdown. This proposal utilizes this system, along with
biochemical and immunological techniques, to 1) identify the domain(s) of CRAF responsible for mediating
tumor regression, 2) determine the downstream effectors necessary for tumor regression, and 3) characterize
the changes within the tumor microenvironment upon CRAF loss. Improved mechanistic understanding of this
phenomenon and successful execution of these aims will lead to novel strategies for targeting KRAS-driven
lung cancers, either as monotherapy or rationally-designed combination therapy, as well as potential
biomarkers predictive of response. Dr. Victoria Wang is mentored by Dr. Frank McCormick, a world expert in
RAS signaling, and will also benefit from an advisory committee comprised of Dr. Dean Sheppard, Dr. David
Carbone, Dr. Matthew Krummel, and Dr. Shiva Malek, who will collectively provide mentorship, collaboration
and expertise in cancer biology, signaling, immunology, and lung cancer translational research. Dr. Wang has
also formulated a comprehensive 5-year training plan that will leverage the outstanding resources available at
UCSF (ranking second in NIH funding among all institutions), incorporating laboratory training, didactic
coursework, scientific meetings and professional development opportunities that will assist her in achieving her
scientific and career goals of developing into an independent, translational lung cancer investigator.