Project Summary/Abstract Exploiting KRAS addiction for lung cancer therapy There is a great unmet need to develop new approaches for KRAS mutant lung cancers. While 25-30% of lung adenocarcinomas arise by virtue of activating KRAS mutations, individual tumors may develop KRAS indifference over the course of cancer progression. It is well-appreciated that cancer cells continue to develop adaptations to support the uncontrolled growth and survival required for tumor progression and metastasis. New data shows that the expression of integrin αvβ3 on KRAS mutant cancer cells predicts which tumors remain dependent on KRAS for tumor growth as well as anchorage-independent growth, a hallmark of cancer that is required for invasion and metastatic spread. While a variety of membrane receptors function by clustering in adherent cells, integrin αvβ3 is unique in its ability to cluster and drive signaling pathways in the absence of extracellular matrix anchoring. The Preliminary Results establish that integrin αvβ3 clustering in non-adherent cells gives rise to KRAS addiction by enabling multiple functions of KRAS that drive stress tolerance, including formation of macropinosomes that facilitate nutrient uptake and promotion of a gene expression program that favors redox balance. The overall goals of this proposal are to define how αvβ3-mediated KRAS clustering promotes survival advantages that drive KRAS addiction and contribute to lung cancer initiation, progression, and metastasis in vivo. Understanding the molecular mechanisms critical for this pathway will foster the design of new therapies to exploit the unique vulnerabilities of KRAS mutant cancers. The Specific Aims of this Multi-PI R01 are designed to understand the cell and molecular biological role for αvβ3 as a regulator of KRAS addiction (Aim 1 – led by Dr. Cheresh) and to learn how this relates to cancer initiation and progression using genetically-engineered mouse models of lung cancer driven by oncogenic Kras (Aim 2 – led by Dr. Onaitis). These findings will enable the logical design of new strategies to target KRAS- addicted cells for cancer therapy (Aim 3 – a collaborative effort). Aim 1: Establish the molecular basis for αvβ3 regulation of KRAS functions in vitro Aim 2: Define the impact of αvβ3 on Kras-driven NSCLC in vivo Aim 3: Exploit KRAS addiction to enhance cancer therapy