Characterization of a drug-resilient cancer cell phenotype [RNA-Seq 2]
Resistance to treatment and post-therapy recurrence due to small populations of resistant cells remain core challenges in cancer therapy. The mechanisms underlying therapy resistance are undefined for many patients. Here, we demonstrate that some cancer cells survive therapeutic stress via a transient state of whole genome doubling. At the onset of the polyploidization program, we identified upregulation of key transcriptional regulators, including the early stress-response protein AP-1 and normoxic stabilization of HIF-2a. Moreover, chromatin accessibility is altered and expression of pRB is ablated, and we identified enrichment of AP-1 motif accessibility along with an upregulation of replication-dependent histone variants. Here we demonstrate that AP-1and HIF-2a regulate a therapy resilient and survivor phenotype in cancer cells. Consistent with this, genetic or pharmacologic targeting of AP-1 and HIF-2a reduced the frequency of surviving cells following treatment with chemotherapy. These results suggest a novel avenue for tackling chemotherapy-induced resistance in cancer. Overall design: To establish a drug resistant populatio we treated cells wit LD50 cisplatin for 72h