Abstract A27: Identification of novel KRAS-synthetic lethal targets for treatment of KRAS-dependent Non-Small Cell Lung Cancer

Lung cancer is the number one cause of cancer-related deaths worldwide. The most prevalent type of lung cancer is Non-Small Cell Lung Cancer (NSCLC). A significant number of patients with NSCLC carry oncogenic KRAS mutations. However, the efforts to target KRAS directly have thus far proven unsuccessful and tumors harboring mutations in this gene remain the most difficult to treat, highlighting the need for alternative approaches. One promising avenue to treat these cancers is to exploit the concept of synthetic lethality.To identify novel KRAS synthetic lethal interactions we performed shRNA gene knock-down screens in 3D cultures of cells derived from a mouse model of NSCLC driven by the activation of KRAS and loss of P53. Growing cells in 3D culture was shown to more faithfully recapitulate important aspects of cancer biology when compared to cells grown as monolayers. In addition, 3D cultures were shown to be enriched in tumor-propagating cells (TPCs), a subset of cells driving tumor initiation, maintenance and progression. We have also previously shown that TPCs contribute to chemoresistance and that the TPC-specific gene signature correlates with poor prognosis in NSCLC patients. Here we used pooled shRNA libraries targeting 623 genes associated with tumor response to chemotherapy, DNA damage response, components of the KRAS interaction network, and KRAS effector genes to screen for potential KRAS-dependent TPC vulnerabilities. As a control we performed the screen in KRA...
Source: Molecular Cancer Therapeutics - Category: Cancer & Oncology Authors: Tags: Finding Synthetic Lethal Interactions through Functional Genomics: Poster Presentations - Proffered Abstracts Source Type: research