Abstract 3852: IK-930, a paralog-selective novel TEAD-inhibitor, effectively attenuates drug-tolerant persister cell proliferation

Abstract

Abstract The Hippo pathway is commonly mutated or altered in human cancers. In addition to the primary genetic driving mutations, the downstream effectors of the Hippo pathway comprising the transcriptional coactivators YAP1 and TAZ and the TEAD transcription factors can be activated upon prolonged inhibition of other oncogenic pathways such as EGFR and MAPK. We showed that combining the novel, paralog selective TEAD inhibitor, IK-930, with osimertinib or trametinib in EGFR or KRAS mutated tumors, led to enhanced apoptosis in vitro and beneficial antitumor activity in vivo. Experimental models demonstrated that upon inhibition of EGFR with osimertinib, a subpopulation of drug tolerant cells defined as ‘persisters’ can survive treatment allowing for the accumulation of additional genetic and epigenetic alterations. These alterations in the persister cells can give rise to resistant tumors and cancer relapse. Previous studies have implicated YAP/TEAD signaling in the emergence and survival of the persister cells. To investigate the role of YAP/TEAD signaling in persister cell emergence, EGFR and KRAS mutant NSCLC cell lines were engineered to express a TEAD luciferase reporter. Treatment with EGFR or MEK inhibitors, at concentrations that do not elicit significant cell death, induced TEAD-mediated transcription after several days of treatment, indicative of an adaptive response to chronic target inhibition. Concurrent treatment with the TEAD inhibitor, IK-930, abolished TEAD-mediated transcription. Using time lapse microscopy, the cell cycle and proliferation of EGFR mutant cultured cells, engineered to express a fluorescence-based cell-cycle indicator (FUCCI), were quantified when treated with osimertinib alone or combined with IK-930. Treatment with osimertinib led to a rapid induction of cell death. However, after several days, a drug tolerant population emerged and reentered the cell cycle even with chronic osimertinib treatment. Interestingly, the emergence of these persister cells coincided with maximum TEAD activity. Concurrent addition of IK-930, as well as addition of IK-930 after the emergence of the osimertinib-tolerant persister cells, attenuated cell proliferation and expansion, demonstrating the potential for IK-930 to prevent resistance to EGFR inhibitors and even reverse the effect when given after resistance has already emerged. Current efforts are focused on the characterization of the persister population and on evaluating the role of YAP/TEAD signaling in resistance to other targeted therapies. Citation Format: Daniel Hidalgo, Marta Sanchez-Martin, Mihir Rajurkar, George Punkosdy, Jeffrey Ecsedy, Lan Xu. IK-930, a paralog-selective novel TEAD-inhibitor, effectively attenuates drug-tolerant persister cell proliferation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3852.