Harnessing transcriptionally driven chromosomal instability adaptation to target therapy-refractory lethal prostate cancer PMID: 36787737

ADC Targets in Oncology

2026-04-10

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].

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.