Deconstruction of Oncogenic K-RAS Signaling Reveals Focal Adhesion Kinase as a Novel Therapeutic Target in NSCLC
Abstract
About 25% of lung adenocarcinomas express mutant KRAS often is association with inactivation of the CDKN2A locus, which comprises p16INK4A and p14ARF or the p53 tumor suppressors. These mutations are associated with disease progression and poor prognosis. There are no therapies that target cancers that express mutant KRAS. We identified a RHOA-Focal adhesion kinase (FAK) axis that is required for the viability of mutant KRAS lung adenocarcinomas that carry INK4A/ARF mutations. This set of mutations is relevant since we determined that it occurs in about half of mutant KRAS lung cancers. We found that pharmacological inhibition of FAK caused tumor regression specifically in high-grade mutant Kras;p16Ink4a/p19Arf null lung cancers in genetically engineered mice and in a large panel of cultured human lung cancer cells. We also found that mutant KRAS;p53 deficient lung cancers are vulnerable to inhibition of FAK, even though to a lesser extent. These findings provided the rationale for the implementation of a multi-institutional Phase II clinical trial using VS-6063 in lung cancer patients with KRAS mutations (PIs Dr. Gerber at UT Southwestern Medical Center). Ongoing work aims at the determining the underpinnings of the dependency of lung cancer cells to FAK both in cultured lung cancer cells and in vivo. In this regards, we found that FAK inhibition impairs the DNA damage response, potentiating the effects of radiotherapy.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2014
- Accession Number
- ADA613426
Entities
People
- Pier P. Scaglioni
Organizations
- University of Texas at Dallas