UCSF

KRAS is a GTPase that transmits external signals into the cell to regulate numerous cellular processes including cell division and apoptosis. Hence mutations in KRAS that render it constitutively active make it a potent oncogene. KRAS driver mutations are found in ~30% of non-small cell lung cancers and are associated with poor prognosis. Because of the significant challenges presented by pharmacological targeting of KRAS, efforts have turned to defining and targeting KRAS-regulated signaling pathways that are required for cancer cell maintenance. Most notable among these are the RAF protein kinases and PI3Kα, which have been credentialed both as key effectors of KRAS and bona fide human oncogenes. To study the contributions of these pathways to lung tumorigenesis I employed genetically engineered mouse models in which mutationally activated KRAS[G12D], BRAF[V600E], or PI3Kα[H1047R] can be conditionally expressed in the lung epithelium. Using these tools and complimentary tissue culture systems I tested the role of PI3Kα signaling in BRAF- and KRAS-driven lung cancer formation. My results show that simultaneous expression of oncogenic BRAF and PI3Kα is sufficient to form lung cancer in mice in a way that mimics KRAS activation. Thus RAF>MEK>ERK and PI3Kα>AKT act synergistically to promote lung tumorigenesis. In addition, mutational activation of PI3Kα dramatically accelerates KRAS-driven lung tumor initiation and progression, showing that despite the known ability of KRAS to directly activate PI3Kα, PI3-lipid signaling remains limiting for KRAS-driven lung tumorigenesis. Finally, the cooperation between oncogenic PI3Kα and BRAF or KRAS can be partially explained by signals downstream of RAF>MEK>ERK and PI3Kα>AKT that converge on activation of the cell division cycle and suppression of apoptosis. However in both BRAF/PIK3CA and KRAS/PIK3CA mutated tumors, PI3K inhibition is cytostatic at best and only moderately slows the growth of cancers, indicating that blockade of this pathway in established tumors suppresses cell division but does not illicit cell death.