TY - JOUR
T1 - Harnessing transcriptionally driven chromosomal instability adaptation to target therapy-refractory lethal prostate cancer
AU - Dhital, Brittiny
AU - Santasusagna, Sandra
AU - Kirthika, Perumalraja
AU - Xu, Michael
AU - Li, Peiyao
AU - Carceles-Cordon, Marc
AU - Soni, Rajesh K.
AU - Li, Zhuoning
AU - Hendrickson, Ronald C.
AU - Schiewer, Matthew J.
AU - Kelly, William K.
AU - Sternberg, Cora N.
AU - Luo, Jun
AU - Lujambio, Amaia
AU - Cordon-Cardo, Carlos
AU - Alvarez-Fernandez, Monica
AU - Malumbres, Marcos
AU - Huang, Haojie
AU - Ertel, Adam
AU - Domingo-Domenech, Josep
AU - Rodriguez-Bravo, Veronica
N1 - Funding Information:
We thank all lab members; the CHTN for tumor specimens; Stephen Elledge for the pInducer20 plasmid; TJU Genomics Core ChIP-seq assistance; Matt Miele and Lisa Mohr for proteomic technical help; Mark Fortini for manuscript proofreading; and the Knudsen lab, S. Barilla, C. Martos-Rus, J. Carter, and V. Miguela for technical help. Research was supported by NIH/NCI grants P30CA08748 (to R.C.H.); R01CA207311 and R01CA261925 (to J.D.-D.); K22CA207458 and R01CA237398 (to V.R.-B.); and funding to V.R.-B. from the Mayo Clinic Foundation, The Margaret Q. Landenberger Research Foundation, The W.W. Smith Charitable Trust, The AACR, and The Prostate Cancer Foundation (PCF). Conceptualization, J.D.-D. and V.R.-B.; methodology, validation, investigation, and analysis, B.D. S.S. K.P. P.L. M.C.-C. M.X. A.E. J.D.-D. and V.R.-B; bioinformatics, A.E.; resources, pathology, clinical relevance, and pre-clinical work assistance, M.M. M.A.-F. A.L. J.L. C.N.S. M.J.S. W.K.K. C.C.-C. H.H. J.D.-D. and V.R.-B.; proteomic support, R.K.S. L.Z. and R.C.H.; writing draft with co-authors’ input, V.R.-B.; draft review and editing, B.D. S.S. M.J.S. M.C.-C. J.D.-D. and V.R.-B.; research supervision, funding acquisition, and project administration, V.R.-B. The authors declare no competing financial interests. One or more of the authors of this paper self-identifies as an under-represented ethnic minority in science, as a gender minority in their field of research and/or received support from a program designed to increase minority representation in science.
Funding Information:
We thank all lab members; the CHTN for tumor specimens; Stephen Elledge for the pInducer20 plasmid; TJU Genomics Core ChIP-seq assistance; Matt Miele and Lisa Mohr for proteomic technical help; Mark Fortini for manuscript proofreading; and the Knudsen lab, S. Barilla, C. Martos-Rus, J. Carter, and V. Miguela for technical help. Research was supported by NIH / NCI grants P30CA08748 (to R.C.H.); R01 CA207311 and R01 CA261925 (to J.D.-D.); K22 CA207458 and R01 CA237398 (to V.R.-B.); and funding to V.R.-B. from the Mayo Clinic Foundation , The Margaret Q. Landenberger Research Foundation , The W.W. Smith Charitable Trust, The AACR, and The Prostate Cancer Foundation (PCF).
Publisher Copyright:
© 2023 The Author(s)
PY - 2023/2/21
Y1 - 2023/2/21
N2 - 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.
AB - 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.
KW - AR-V7
KW - chromosomal instability (CIN)
KW - E2F7
KW - lethal prostate cancer
KW - MASTL
KW - therapy resistance
UR - http://www.scopus.com/inward/record.url?scp=85148335176&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85148335176&partnerID=8YFLogxK
U2 - 10.1016/j.xcrm.2023.100937
DO - 10.1016/j.xcrm.2023.100937
M3 - Article
C2 - 36787737
AN - SCOPUS:85148335176
SN - 2666-3791
VL - 4
JO - Cell Reports Medicine
JF - Cell Reports Medicine
IS - 2
M1 - 100937
ER -