ATR Inhibitor M6620 (VX-970) Enhances the Effect of Radiation in Non-Small Cell Lung Cancer Brain Metastasis Patient-Derived Xenografts

Authors

Andrew M. Baschnagel, University of Wisconsin School of Medicine and Public Health
Jacob H. Elnaggar, LSU Health Sciences Center- New OrleansFollow
Haley J. VanBeek, University of Wisconsin School of Medicine and Public Health
Ashley C. Kromke, University of Wisconsin School of Medicine and Public Health
Justin H. Skiba, University of Wisconsin School of Medicine and Public Health
Saakshi Kaushik, University of Wisconsin School of Medicine and Public Health
Lindsey Abel, University of Wisconsin School of Medicine and Public Health
Paul A. Clark, University of Wisconsin School of Medicine and Public Health
Colin A. Longhurst, University of Wisconsin School of Medicine and Public Health
Kwangok P. Nickel, University of Wisconsin School of Medicine and Public Health
Ticiana A. Leal, University of Wisconsin Carbone Cancer Center
Shuang G. Zhao, University of Wisconsin School of Medicine and Public Health
Randall J. Kimple, University of Wisconsin School of Medicine and Public Health

Document Type

Article

Publication Date

11-1-2021

Publication Title

Molecular Cancer Therapeutics

Abstract

M6620, a selective ATP-competitive inhibitor of the ATM and RAD3-related (ATR) kinase, is currently under investigation with radiation in patients with non-small cell lung cancer (NSCLC) brain metastases. We evaluated the DNA damage response (DDR) pathway profile of NSCLC and assessed the radiosensitizing effects of M6620 in a preclinical NSCLC brain metastasis model. Mutation analysis and transcriptome profiling of DDR genes and pathways was performed on NSCLC patient samples. NSCLC cell lines were assessed with proliferation, clonogenic survival, apoptosis, cell cycle, and DNA damage signaling and repair assays. NSCLC brain metastasis patient-derived xenograft models were used to assess intracranial response and overall survival. In vivo IHC was performed to confirm in vitro results. A significant portion of NSCLC patient tumors demonstrated enrichment of DDR pathways. DDR pathways correlated with lung squamous cell histology; and mutations in ATR, ATM, BRCA1, BRCA2, CHEK1, and CHEK2 correlated with enrichment of DDR pathways in lung adenocarcinomas. M6620 reduced colony formation after radiotherapy and resulted in inhibition of DNA DSB repair, abrogation of the radiation-induced G2 cell checkpoint, and formation of dysfunctional micronuclei, leading to enhanced radiation-induced mitotic death. The combination of M6620 and radiation resulted in improved overall survival in mice compared with radiation alone. In vivo IHC revealed inhibition of pChk1 in the radiation plus M6620 group. M6620 enhances the effect of radiation in our preclinical NSCLC brain metastasis models, supporting the ongoing clinical trial (NCT02589522) evaluating M6620 in combination with whole brain irradiation in patients with NSCLC brain metastases.

First Page

2129

Last Page

2139

PubMed ID

34413128

Volume

20

Issue

11

Publisher

American Association for Cancer Research

Recommended Citation

Baschnagel, Andrew M.; Elnaggar, Jacob H.; VanBeek, Haley J.; Kromke, Ashley C.; Skiba, Justin H.; Kaushik, Saakshi; Abel, Lindsey; Clark, Paul A.; Longhurst, Colin A.; Nickel, Kwangok P.; Leal, Ticiana A.; Zhao, Shuang G.; and Kimple, Randall J., "ATR Inhibitor M6620 (VX-970) Enhances the Effect of Radiation in Non-Small Cell Lung Cancer Brain Metastasis Patient-Derived Xenografts" (2021). School of Graduate Studies Faculty Publications. 19.
https://digitalscholar.lsuhsc.edu/sogs_facpubs/19