Abstract 2004: CDC7 inhibition prevents neuroendocrine transformation in the lung and prostate through MYC degradation
Authors: Quintanal-Villalonga Alvaro , Uddin Fathema , Kawasaki Kenta , Redin Esther , Durani Vidushi , Sabet Amin , Karthaus Wouter , Zhan Yingqian A. , Zaidi Samir , Shaffer Moniquetta , Sridhar Harsha , Qiu Juan , Manoj Parvathy , De Stanchina Elisa , Haffner Michael C. , Sawyers Charles L. , Rudin Charles M. 
Published: March 2024

Abstract
Neuroendocrine (NE) transformation occurs as a mechanism of resistance to targeted therapy in up to 14% and 30% of EGFR-mutant lung and AR-dependent prostate adenocarcinomas, respectively, leading to poor prognosis. Even if we know the tumor population at high risk of transformation (TP53/RB1-mutated), no therapies to prevent NE relapse are currently available. To identify therapeutic vulnerabilities for tumors undergoing NE transformation, we performed an in vitro CRISPR screen in a NE-transformed lung tumor model. This screen identified CDC7, involved in DNA replication and DNA damage response, as a potential therapeutic target in this setting. Proteogenomic analyses revealed CDC7 upregulation in lung and prostate clinical samples undergoing NE transformation, detected already in pre-transformation adenocarcinomas. These results indicated that CDC7 expression is induced already at early steps of transformation. Consistently, TP53/RB1-mutated lung and prostate adenocarcinomas exhibited higher CDC7 expression than their double wild-type counterparts. Combined ChIP-seq and promoter reporter assays indicated that CDC7 expression was directly regulated by TP53 and RB1 inactivation. Importantly, TP53/RB1-inactivation induced sensitivity to the CDC7 inhibitor simurosertib, unraveling a therapeutic vulnerability in tumors at high risk of NE transformation. Thus, we tested the combination of simurosertib with targeted therapy in vivo in different lung and prostate patient-derived models of NE transformation, namely TP53/RB1-knock out adenocarcinomas known to undergo NE transformation on targeted therapy. In these, simurosertib was able to suppress NE transformation and dramatically delay tumor relapse. Trajectory analysis on single-cell transcriptomic data for such models revealed a NE transformation transcriptional program occurring already in the untreated tumors before transformation. Remarkably, simurosertib treatment reverted this transcriptomic state and induced a reversion to the original adenocarcinoma transcriptomic profile. CDC7 inhibition led to increased proteasomal activity and degradation of MYC, a stemness transcription factor involved in NE transformation. Ectopic overexpression of MYCT58A, a proteasome degradation-resistant MYC isoform, rescued the NE phenotype in these transformation models, suggesting that CDC7 inhibition-induced MYC degradation is the mechanism by which NE transformation is prevented. In sum, CDC7 inhibition may suppress, or at least dramatically delay NE transformation in patients with lung and prostate adenocarcinomas at high risk of transformation, by inducing MYC proteasomal degradation. The clinical availability of CDC7 inhibitors, currently in phase II clinical trials after demonstrating tolerability and preliminary efficacy, will allow rapid translation of these results into the clinics.
Citation Format: Alvaro Quintanal-Villalonga, Fathema Uddin, Kenta Kawasaki, Esther Redin, Vidushi Durani, Amin Sabet, Wouter Karthaus, Yingqian A. Zhan, Samir Zaidi, Moniquetta Shaffer, Harsha Sridhar, Juan Qiu, Parvathy Manoj, Elisa De Stanchina, Michael C. Haffner, Charles L. Sawyers, Charles M. Rudin. CDC7 inhibition prevents neuroendocrine transformation in the lung and prostate through MYC degradation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2004.