Redefining KRAS dependency as a stress-inducible state

While smoking is well-known as a contributor to more than 80% of lung cancer deaths, it is also one of the most important risk factors for pancreatic cancer, a disease characterized by a dismal 5-year survival rate of <10%.  Despite the great advances in understanding what molecular pathways these cancers use to develop and progress, certain types of tumors continue to escape the effects of therapy.  Our proposal focuses on one such unmet need:  the subset of lung and pancreatic cancers harboring KRAS mutations. 

Even though “oncogenic KRAS” is required for the formation of 25% of lung cancers and 95% of pancreatic ductal adenocarcinoma cases, strategies to target KRAS have not met with clinical success.  We propose to develop new therapeutic options for this subset by identifying how and why certain tumors remain “addicted” to KRAS during tumor progression.  By understanding the biology underlying the aggressive nature of these tumors, we will be able to identify new strategies to target their unique susceptibilities.  In particular, we recently discovered that expression of integrin alpha-v beta-3 predicts which cancer cells cannot survive without KRAS.  We think that this is because integrin alpha-v beta-3 can recruit KRAS into signal-generating clusters that provide cells with several important ways to survive within the inhospitable tumor microenvironment. 

In order to translate these cell biological findings into clinical impact, we need to understand what factors influence the expression of integrin alpha-v beta-3, and to define how KRAS functions differently when integrin alpha-v beta-3 is present.  We propose that answering these key questions will reveal unique vulnerabilities, and thus therapeutic opportunities, for a class of lung and pancreatic cancers that harbor KRAS mutations.  If successful, our project will provide a preclinical rationale for developing new therapeutic strategies for these smoking-related cancers with a devastating survival rate.