Research Summary: Targeting KRAS-mutant NSCLC through inhibition of mTOR and Hsp90

Grant Recipient: Dr. Timothy F. Burns
Title of Project: Targeting KRAS-mutant NSCLC through inhibition of mTOR and Hsp90
Sponsoring Institution:
University of Pittsburgh Cancer Institute, Pittsburgh, PA

Lung cancer is the leading cause of cancer death in the United States and worldwide. In non-small cell lung cancer (NSCLC), a protein called KRAS often becomes inappropriately turned on and causes a tumor to grow. Patients with KRAS-mutated lung cancer have a poor prognosis and no current therapies target this critical oncogene. Our goal is to develop novel therapies for patients with KRAS mutant lung cancer. In this proposal, we focus on a therapy that can inhibit multiple signaling pathways downstream of KRAS that are required for KRAS mutant tumors to grow. We have found in a clinical trial that some of the KRAS mutant tumors shrink when treated with a novel Hsp90 inhibitor, ganetespib. In Aim 1 of this grant we will identify what makes some KRAS mutant tumors respond initially to ganetespib and then become resistant. These studies will identify targeted therapeutics agents that could be combined with ganetespib to overcome resistance to ganetespib alone. Furthermore, we have recently shown that the combination of an Hsp90 inhibitor, ganetespib, and an mTOR inhibitor is effective in KRAS mutant tumor cell lines. In Aim 2, we will examine candidate biomarkers of response to this combination so that we can test these biomarkers in the third aim of our grant, a Phase I/II clinical trial of the combination of ganetespib and an mTOR inhibitor in patients with KRAS mutant NSCLC. This translational approach will allow us to target this combination to the patients who are likely to respond.