Abstract
BackgroundHyperactivation of the Ras signaling pathway is a driver of many cancers, and RAS pathway activation can predict response to targeted therapies. Therefore, optimal methods for measuring Ras pathway activation are critical. The main focus of our work was to develop a gene expression signature that is predictive of RAS pathway dependence.MethodsWe used the coherent expression of RAS pathway-related genes across multiple datasets to derive a RAS pathway gene expression signature and generate RAS pathway activation scores in pre-clinical cancer models and human tumors. We then related this signature to KRAS mutation status and drug response data in pre-clinical and clinical datasets.ResultsThe RAS signature score is predictive of KRAS mutation status in lung tumors and cell lines with high (> 90%) sensitivity but relatively low (50%) specificity due to samples that have apparent RAS pathway activation in the absence of a KRAS mutation. In lung and breast cancer cell line panels, the RAS pathway signature score correlates with pMEK and pERK expression, and predicts resistance to AKT inhibition and sensitivity to MEK inhibition within both KRAS mutant and KRAS wild-type groups. The RAS pathway signature is upregulated in breast cancer cell lines that have acquired resistance to AKT inhibition, and is downregulated by inhibition of MEK. In lung cancer cell lines knockdown of KRAS using siRNA demonstrates that the RAS pathway signature is a better measure of dependence on RAS compared to KRAS mutation status. In human tumors, the RAS pathway signature is elevated in ER negative breast tumors and lung adenocarcinomas, and predicts resistance to cetuximab in metastatic colorectal cancer.ConclusionsThese data demonstrate that the RAS pathway signature is superior to KRAS mutation status for the prediction of dependence on RAS signaling, can predict response to PI3K and RAS pathway inhibitors, and is likely to have the most clinical utility in lung and breast tumors.
Highlights
Hyperactivation of the Ras signaling pathway is a driver of many cancers, and RAS pathway activation can predict response to targeted therapies
We show that baseline levels of the RAS pathway signature predict resistance to AKT inhibition and sensitivity to MEK inhibition in cell line panels independent of KRAS mutation status, that the signature is downregulated by MEK inhibition, and that the signature is a better predictor of RAS pathway dependence compared to KRAS mutation status in lung cancer cell lines
We find that this RAS pathway signature is a high sensitivity but low specificity predictor of KRAS mutation status, as many cell line and tumor samples appear to have RAS pathway activation in the absence of mutations in KRAS
Summary
Hyperactivation of the Ras signaling pathway is a driver of many cancers, and RAS pathway activation can predict response to targeted therapies. Signal transduction in response to growth factor receptor activation in tumors is a complex process that involves downstream signaling through the RAS (reviewed in [1]) and PI3K (reviewed in [2]) signaling pathways. These changes in PTEN, PIK3CA, AKT, KRas and BRAF, all of which have been shown to contribute to the cancer phenotype. While alterations in specific RAS pathway components have lead to an increased understanding of the molecular drivers of response to EGFR inhibition in colorectal cancer, the relationship between KRAS mutation, RAS pathway dependence, and drug response is less clear in NSCLC and other tumor types
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
