Abstract B13: Parallel targeting of RAF/MEK/ERK pathway in RAS-mutant embryonal rhabdomyosarcoma

Abstract

Abstract Recent sequencing of childhood rhabdomyosarcoma identified the presence of RAS pathway mutations in nearly 75% of high-risk embryonal rhabdomyosarcoma (ERMS). While RAS oncoproteins (HRAS, NRAS and KRAS) are well-established therapeutic targets for many adult human cancers, still very little is known about the role of RAS mutations in the development and maintenance of ERMS. We sequenced ERMS cell lines and PDX tumors and identified 4 cell lines harboring activating mutations in H- or NRAS and two cell lines with wild-type RAS. By siRNA mediated knockdown, we showed that mutant H- or NRAS was critical for the growth of all RAS-mutant ERMS cell lines and that RAF/MEK/ERK signaling pathway, but not PI3K/AKT, was mediator of RAS dependency in these cells. However, in vivo treatment of RAS-mutant ERMS xenografts with the MEK inhibitor trametinib showed modest response as compared to BRAF-mutant astrocytoma xenografts. We reasoned that similarly to other RAS-driven cancers, ERMS tumors are able to acquire resistance to inhibitors of the RAF/MEK/ERK pathway. We performed CRISPR screen and identified that inhibition of ERK2 potentiated trametinib treatment. We show that combining trametinib with ERK1/2 inhibitor leads to potent synergistic MEK/ERK pathway inhibition and ERMS tumor growth suppression. Citation Format: Angelina V. Vaseva, Abhik Bandyopadhyay, Vanessa Del Pozzo, Craig M. Goodwin, Prson Gautam, Krister Wennerberg, Kris C. Wood, Channing J. Der, Peter J. Houghton. Parallel targeting of RAF/MEK/ERK pathway in RAS-mutant embryonal rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr B13.