Abstract P216: IK-930 mediated TEAD inhibition decreases and delays tumor growth and enhances targeted apoptosis in lung and colon cancer xenografts when combined with MEK or EGFR inhibitors

Abstract

Abstract The Hippo signaling cascade is an important pathway that plays a role in controlling cell proliferation and limiting apoptosis, but when dysregulated can contribute to cancer initiation, progression, and therapeutic resistance. The TEAD family of transcription factors, in conjunction with YAP1 or WWTR1/TAZ, are regulated by Hippo pathway signaling and modulate cell growth and proliferation. IK-930 inhibits the growth of TEAD-dependent human cancer xenografts. By exploiting synthetic lethality, the IK-930 single agent activity in TEAD-dependent cancers could expand to other indications upon inhibition of certain oncogenic pathways. Literature indicates that activation of TEAD-dependent transcription by other oncogenes such as mutant EGFR or KRAS mediates resistance to multiple targeted therapies. Additionally, genetic loss of YAP1 leads to increased apoptosis in osimertinib and trametinib treated mutant EGFR NSCLC cell lines (Kurppa, 2020). Here, we present preclinical data that support the use of IK-930 combination therapies to enhance anti-tumor impact of EGFR and MEK blockade in mutant EGFR NSCLC, or with MEK inhibition in several BRAF and KRAS mutant cancers. In these studies, EGFR and MEK1/2 were inhibited and IK-930 used to enhance anti-tumor activity in EGFR-mutant NSCLC cells. These NSCLC cell lines that are largely insensitive to osimertinib and/or trametinib, were observed to have a marked increase in apoptosis in vitro when treated with the combination of osimertinib, trametinib, and IK-930. We also observed increased nuclear accumulation of YAP1 after treatment of NSCLC cells with osimertinib alone, or osimertinib and trametinib and upregulation of TEAD-dependent transcription. In NSCLC xenografts, the combination of osimertinib and IK-930 prevented tumor growth and the triple combination of osimertinib, IK-930, and trametinib drove complete tumor regression and demonstrated greater efficacy than any single agent or double combination. A second set of studies tested the synthetic lethality effect of IK-930 and MEK inhibition in RAF- and RAS-mutant tumors. The combination of TEAD inhibition with MEK inhibition enhanced apoptosis in several KRAS-mutant NSCLC, PDAC, CRC KRAS-mutant cell lines and BRAF-mutant melanoma. The combination of trametinib and IK-930 prevented tumor growth in these xenografts, where either single agent had either modest or little activity. In summary, the Hippo pathway has been implicated in multiple tumor types, including those with resistance mechanisms to EGFR and MEK blockade. IK-930-mediated TEAD inhibition has been investigated to suppress the bypass pathway activation mechanism to the targeted therapies. These data demonstrated the potential to further expand single agent patient benefit by combining IK-930 with MEK and/or EGFR inhibition in a wide variety of cancer indications, including mutant EGFR-driven NSCLC and mutant KRAS colon, lung, and pancreatic cancers. Taken together, these data are informing the clinical development plan and combination strategy for IK-930, a novel TEAD inhibitor. Citation Format: Benjamin Amidon, Hyejin Frosch, Sakeena Syed, Jill Cavanaugh, Chelsea Turcotte, Katie O'Callaghan, Prabitha Natarajan, Jeffrey Ecsedy, Karen McGovern, Alfredo Castro. IK-930 mediated TEAD inhibition decreases and delays tumor growth and enhances targeted apoptosis in lung and colon cancer xenografts when combined with MEK or EGFR inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P216.