Funding
EC | Horizon 2020 Framework Programme (H2020)
Cancerfonden (Swedish Cancer Society)
Barncancerfonden (Swedish Childhood Cancer Foundation)
Vetenskapsrådet (VR)
Governmental Funding of Clinical Research within the National Health Service
DOD | USA | MEDCOM | Congressionally Directed Medical Research Programs (CDMRP)
DOD | USA | MEDCOM | CDMRP | DOD Prostate Cancer Research Program (PCRP)
Patrick C. Walsh Prostate Cancer Research Fund (Patrick C Walsh Prostate Cancer Research Fund)
Prostate Cancer Foundation (PCF)
HHS | NIH | National Cancer Institute (NCI)
Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation)
Svenska Sällskapet för Medicinsk Forskning (SSMF)
UKRI | MRC | Medical Research Foundation
Kungliga Fysiografiska Sällskapet i Lund (Royal Physiographic Society in Lund)
Crafoordska Stiftelsen (The Crafoord Foundation)
ARTICLE ABSTRACT
Therapeutic resistance and recurrence remain core challenges in cancer therapy. How therapy resistance arises is currently not fully understood with tumors surviving via multiple alternative routes. Here, we demonstrate that a subset of cancer cells survives therapeutic stress by entering a transient state characterized by whole-genome doubling. At the onset of the polyploidization program, we identified an upregulation of key transcriptional regulators, including the early stress-response protein AP-1 and normoxic stabilization of HIF2α. We found altered chromatin accessibility, ablated expression of retinoblastoma protein (RB1), and enrichment of AP-1 motif accessibility. We demonstrate that AP-1 and HIF2α regulate a therapy resilient and survivor phenotype in cancer cells. Consistent with this, genetic or pharmacologic targeting of AP-1 and HIF2α reduced the number of surviving cells following chemotherapy treatment. The role of AP-1 and HIF2α in stress response by polyploidy suggests a novel avenue for tackling chemotherapy-induced resistance in cancer.
In response to cisplatin treatment, some surviving cancer cells undergo whole-genome duplications without mitosis, which represents a mechanism of drug resistance. This study presents mechanistic data to implicate AP-1 and HIF2α signaling in the formation of this surviving cell phenotype. The results open a new avenue for targeting drug-resistant cells.
