Abstract B56: Tracing synthetic rescue reprogramming to counteract cancer resistance
Authors: Sahu Avinash D. , Lee Joo Sang , Hannenhalli Sridhar , Ruppin Eytan 
Published: May 2016

Introduction: Numerous anti-cancer drugs that show promising initial response but eventually develop resistance. Adaptive response is one of the mechanisms of the emergence of resistance, as in the case of Lapatinib, where kinase reprogramming overcomes the ERBB2 inhibition. Such adaptive response belongs to a class of cellular reprogramming events called Synthetic Rescues (SR), where changes in the activity state of one (vulnerable) gene are lethal to the cell and they evade the lethality by reprogramming the activity state of other gene(s) (rescuer).

Aim: We aim to identify the pan cancer genome-scale SR network and demonstrate that such rescue reprogramming is widespread in cancer and is crucial for predicting drug response and deciphering the emergence of drug resistance.

Results: We develop a novel data driven approach, termed “IdeNtification of ClinIcal Synthetic Rescues in cancer”(INCISOR), to identify genome-scale SR network. Analyzing gene-expression, copy number variation and clinical data of 7,550 patients across 23 different cancer types from the TCGA collection, we identify four major classes of SR reprogramming, which involve: two inactive genes (DD), an inactive vulnerable gene and an overactive rescuer (DU), an overactive vulnerable gene and an inactive rescuer (UD), and two overactive genes (UU). Many of these are prevalent across many cancer types, however some are specific to individual cancer types. We further identified SR networks specific to breast cancer. Using an independent patient dataset, we show that patient's survival is highly determined by the number of functionally activated SRs belonging to each of four SR classes, with DU class showing the highest clinical significance among them. Analysis of somatic mutation in TCGA revealed the preferential over-activation of (DU) rescuers as a response to the inactivation of their vulnerable partners by somatic mutations, providing an independent validation of our predictions. We successfully predicted, for the first time, patient response to 72% of (26 out of 36) major breast cancer drugs using the pan cancer (DU) SR network. We find that as cancer progresses, the number of inactivated vulnerable genes that are rescued increases, suggesting a correlation between the level of SR reprogramming and tumor's aggressiveness. Importantly, using multiple patient data we show that the pan cancer SR networks are predictive of emergence of resistance to anthracyclines, taxanes, fluorouracil, olarip, carbolplatin and cyclophasmide in breast, gastric and ovarian cancer. DU-rescuers of the drug targets are markedly over-expressed in post-treatment samples from patients that acquired resistance.

Conclusions: We introduce and rigorously define a new concept of synthetic rescue reprogramming occurring in cancer and present its first genome-wide SR networks. Our analysis shows that molecular reprogramming due to SR is widespread and of considerable clinical importance. The SR networks uncovered provide new insights into the specific molecular mechanisms underlying the emerging resistance to cancer drugs and are predictive of the variable response among patients. Last and not least, our study identifies key rescuer hub genes whose targeting can mitigate the emergence of resistance, offering a new class of candidate drug targets for adjuvant cancer therapies aimed at counteracting resistance.

Citation Format: Avinash D. Sahu, Joo Sang Lee, Sridhar Hannenhalli, Eytan Ruppin. Tracing synthetic rescue reprogramming to counteract cancer resistance. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B56.