Harnessing transcriptionally driven chromosomal instability adaptation to target therapy-refractory lethal prostate cancer

Cell Rep Med. 2023 Feb 21;4(2):100937. doi: 10.1016/j.xcrm.2023.100937.

Brittiny Dhital ¹, Sandra Santasusagna ², Perumalraja Kirthika ², Michael Xu ³, Peiyao Li ³, Marc Carceles-Cordon ⁴, Rajesh K Soni ⁵, Zhuoning Li ⁵, Ronald C Hendrickson ⁵, Matthew J Schiewer ³, William K Kelly ³, Cora N Sternberg ⁶, Jun Luo ⁷, Amaia Lujambio ⁸, Carlos Cordon-Cardo ⁹, Monica Alvarez-Fernandez ¹⁰, Marcos Malumbres ¹¹, Haojie Huang ², Adam Ertel ³, Josep Domingo-Domenech ¹², Veronica Rodriguez-Bravo ¹³

Affiliations

1 Biochemistry and Molecular Biology Department, Mayo Clinic, Rochester, MN 55905, USA; Urology Department, Mayo Clinic, Rochester, MN 55905, USA; Thomas Jefferson University, Sidney Kimmel Cancer Center, Philadelphia, PA 19107, USA.
2 Biochemistry and Molecular Biology Department, Mayo Clinic, Rochester, MN 55905, USA; Urology Department, Mayo Clinic, Rochester, MN 55905, USA.
3 Thomas Jefferson University, Sidney Kimmel Cancer Center, Philadelphia, PA 19107, USA.
4 Urology Department, Mayo Clinic, Rochester, MN 55905, USA.
5 Microchemistry and Proteomics Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
6 Englander Institute for Precision Medicine, Weill Cornell Department of Medicine, Meyer Cancer Center, New York-Presbyterian Hospital, New York, NY 10021, USA.
7 Urology Department, Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
8 Oncological Sciences Department, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
9 Pathology Department, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
10 Head & Neck Cancer Department, Institute de Investigación Sanitaria Principado de Asturias (ISPA), Institute Universitario de Oncología Principado de Asturias (IUOPA), 33011 Oviedo, Spain.
11 Cell Division & Cancer Group, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain; Cancer Cell Cycle group, Vall d'Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
12 Biochemistry and Molecular Biology Department, Mayo Clinic, Rochester, MN 55905, USA; Urology Department, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: [email protected].
13 Biochemistry and Molecular Biology Department, Mayo Clinic, Rochester, MN 55905, USA; Urology Department, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: [email protected].

PMID: 36787737 DOI: 10.1016/j.xcrm.2023.100937

Abstract

Metastatic prostate Cancer (PCa) inevitably acquires resistance to standard therapy preceding lethality. Here, we unveil a chromosomal instability (CIN) tolerance mechanism as a therapeutic vulnerability of therapy-refractory lethal PCa. Through genomic and transcriptomic analysis of patient datasets, we find that castration and chemotherapy-resistant tumors display the highest CIN and mitotic kinase levels. Functional genomics screening coupled with quantitative phosphoproteomics identify MASTL kinase as a survival vulnerability specific of chemotherapy-resistant PCa cells. Mechanistically, MASTL upregulation is driven by transcriptional rewiring mechanisms involving the non-canonical transcription factors Androgen Receptor splice variant 7 and E2F7 in a circuitry that restrains deleterious CIN and prevents cell death selectively in metastatic therapy-resistant PCa cells. Notably, MASTL pharmacological inhibition re-sensitizes tumors to standard therapy and improves survival of pre-clinical models. These results uncover a targetable mechanism promoting high CIN adaptation and survival of lethal PCa.

Keywords

AR-V7; E2F7; MASTL; chromosomal instability (CIN); lethal prostate cancer; therapy resistance.

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99.89%, Greatwall Kinase Inhibitor

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