RhoA as a Potential Target in Lung Cancer

Many cancers are driven by oncogenic K-Ras, yet K-Ras has remained largely undruggable. In this dissertation we explore inhibiting K-Ras signaling by targeting downstream signaling pathways, namely the RhoA and RhoC GTPase pathways. Numerous cellular studies have indicated that RhoA signaling is required for oncogenic Ras-induced transformation. To date very limited data exist to genetically attribute RhoA function to Ras-mediated tumorigenesis in mammalian models. In order to assess whether RhoA is required for K-Ras-induced lung cancer initiation, we utilized the K-RasG12D Lox-Stop-Lox murine lung cancer model in combination with the conditional RhoAflox/flox and RhoC-/- knockout mouse models. We found that deletion of RhoA, RhoC or both did not adversely affect normal lung development. Moreover, we found that deletion of either RhoA or RhoC alone did not suppress K-RasG12D induced lung adenoma initiation. Rather, deletion of RhoA alone increased lung adenoma formation, whereas dual deletion of RhoA and RhoC together significantly reduced K-RasG12D induced adenoma formation. Deletion of RhoA appears to induce a compensatory mechanism that exacerbates adenoma formation. The compensatory mechanism is at least partly mediated by RhoC. These results are in contrast to RhoA knockdown experiments we performed in human lung cancer cell lines, which show dramatic inhibition of malignant phenotypes with RhoA loss. Taken together, this dissertation work suggests that targeting of RhoA alone may allow for compensation and a paradoxical exacerbation of neoplasia, while simultaneous targeting of both RhoA and RhoC is more likely to inhibit oncogenic K-Ras driven lung cancers.