Abstract 839: YES1 is a novel druggable oncogene in small cell lung cancer

Abstract

Abstract Small cell lung cancer (SCLC) is a high-grade neuroendocrine subtype of lung cancer. This tumor is characterized by its aggressiveness, refractoriness to therapies, poor prognosis, and early dissemination. The first line of treatment consists of platinum-based chemotherapy, and although patients initially respond very well to this therapy, they promptly develop resistance. Currently, there are no targeted therapies approved for the treatment of SCLC patients. Here, we identified YES1, a non-receptor tyrosine kinase, as a novel targetable candidate with a relevant role in SCLC. In silico analysis revealed that YES1 is overexpressed in SCLC patients compared to non-malignant lung tissues. In a multi-institutional cohort of 80 SCLC patients, 31% of cases showed high YES1 protein expression and 26% of all specimens had YES1 gain/amplification (CNV≥2.5), analyzed by immunohistochemistry and FISH, respectively. In addition, high expression of YES1 predicted both lower overall survival (OS) and progression free survival (PFS) (n=80). In accordance, YES1 mRNA expression significantly correlated with YES1 CNV in SCLC cell lines. We knocked-down YES1 in two human SCLC cell lines (DMS53 and H209) with high expression and amplification of YES1. Depletion of YES1 almost totally abrogated cell proliferation and the formation of cell line-derived organoids in 3D. Accordingly, inhibition of YES1 arrested the cell cycle and promoted cell apoptosis in vitro. Consistent with these results, knockdown of YES1 promoted a dramatic reduction of subcutaneous tumor growth in both models with high levels of YES1, leading to a rate of partial regression of 54% and 23% complete regression. A metastasis assay, performed by intracardiac injection of H209 cells, showed that inhibition of YES1 led to complete disappearance of metastatic lung, leg and liver tumors in 4 out of 5 mice. Gene set enrichment analysis (GSEA) of RNA sequencing data performed with YES1-depleted DMS53 cells revealed that cells lacking YES1 had a downregulation in DNA replication and DNA repair signatures. We next explored the effect of pharmacological inhibition of YES1 using the multityrosine kinase inhibitor dasatinib and the selective YES1 inhibitor CH6953755. Dasatinib and CH6953755 effectively reduced cell proliferation in vitro at doses <1000 nM in the YES-high lines in contrast to the H69 cell line (low expression of YES1, >10µM). More interestingly, dasatinib and CH6953755 decreased DMS53, H209 and a high-YES1 PDX (YU-16)-derived organoid growth. Pharmacological inhibition of YES1 significantly reduced the tumor growth of high-YES1 models: DMS53 and H209 xenografts, and TP135 and YU-16 PDXs, in contrast to low-YES1 models (H69 xenograft and YU-34 PDX). Our results provide evidence that YES1 is a new druggable oncogenic target in SCLC and that its inhibition could be a promising therapeutic strategy for a subset of patients with high YES1 expression or copy number gain/amplification. Citation Format: Esther Redin, Eva M. Garrido-Martin, Karmele Valencia, Miriam Redrado, Jose Luis Solorzano, Rafael Carias, Franscisco Exposito, Diego Serrano, Nerea Otegui, Luis Paz Ares, Katerina Politi, Luis M. Montuenga, Alfonso Calvo. YES1 is a novel druggable oncogene in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 839.