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New Synthetic Lethality Re-Sensitizing Platinum-Refractory Cancer Cells to Cisplatin In Vitro: The Rationale to Co-Use PARP and ATM Inhibitors
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New Synthetic Lethality Re-Sensitizing Platinum-Refractory Cancer Cells to Cisplatin In Vitro: The Rationale to Co-Use PARP and ATM Inhibitors
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Journal Article
New Synthetic Lethality Re-Sensitizing Platinum-Refractory Cancer Cells to Cisplatin In Vitro: The Rationale to Co-Use PARP and ATM Inhibitors
2021
Overview
The pro-apoptotic tumor suppressor BIN1 inhibits the activities of the neoplastic transcription factor MYC, poly (ADP-ribose) polymerase-1 (PARP1), and ATM Ser/Thr kinase (ATM) by separate mechanisms. Although BIN1 deficits increase cancer-cell resistance to DNA-damaging chemotherapeutics, such as cisplatin, it is not fully understood when BIN1 deficiency occurs and how it provokes cisplatin resistance. Here, we report that the coordinated actions of MYC, PARP1, and ATM assist cancer cells in acquiring cisplatin resistance by BIN1 deficits. Forced BIN1 depletion compromised cisplatin sensitivity irrespective of Ser15-phosphorylated, pro-apoptotic TP53 tumor suppressor. The BIN1 deficit facilitated ATM to phosphorylate the DNA-damage-response (DDR) effectors, including MDC1. Consequently, another DDR protein, RNF8, bound to ATM-phosphorylated MDC1 and protected MDC1 from caspase-3-dependent proteolytic cleavage to hinder cisplatin sensitivity. Of note, long-term and repeated exposure to cisplatin naturally recapitulated the BIN1 loss and accompanying RNF8-dependent cisplatin resistance. Simultaneously, endogenous MYC was remarkably activated by PARP1, thereby repressing the BIN1 promoter, whereas PARP inhibition abolished the hyperactivated MYC-dependent BIN1 suppression and restored cisplatin sensitivity. Since the BIN1 gene rarely mutates in human cancers, our results suggest that simultaneous inhibition of PARP1 and ATM provokes a new BRCAness-independent synthetic lethal effect and ultimately re-establishes cisplatin sensitivity even in platinum-refractory cancer cells.
Publisher
MDPI AG,MDPI
Subject
/ Ataxia Telangiectasia Mutated Proteins - antagonists & inhibitors
/ Ataxia Telangiectasia Mutated Proteins - metabolism
/ Drug Resistance, Neoplasm - drug effects
/ Drug Resistance, Neoplasm - genetics
/ Humans
/ Kinases
/ Mutation
/ Neoplasm Proteins - antagonists & inhibitors
/ Neoplasm Proteins - genetics
/ Neoplasm Proteins - metabolism
/ Poly (ADP-Ribose) Polymerase-1 - antagonists & inhibitors
/ Poly (ADP-Ribose) Polymerase-1 - genetics
/ Poly (ADP-Ribose) Polymerase-1 - metabolism
/ Poly(ADP-ribose) Polymerase Inhibitors - chemistry
/ Poly(ADP-ribose) Polymerase Inhibitors - pharmacology
/ Protein Kinase Inhibitors - chemistry
