New Synthetic Lethality Re-Sensitizing Platinum-Refractory Cancer Cells to Cisplatin In Vitro: The Rationale to Co-Use PARP and ATM Inhibitors.

Watson P Folk,Elizabeth Martin,Erica K Cassimere,Alpana Kumari,Tetsushi Iwasaki,Kelly Homlar,Slovénie Pyndiah,Daitoku Sakamuro

doi:10.3390/ijms222413324

Abstract

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.

Highlights

Rosenberg et al discovered the potent anti-cell division property of cis-diammine dichloro platinum first in Escherichia coli and in tumor cells in the 1960s [1,2]
A small arrow indicates a proteolytically cleaved product, which can be rescued by z-VAD-fmk; (E) KU-60019 (3.0 μM, 72 h) compromises the sh-BIN1induced cisplatin resistance; (F) we propose that the mediator of DNA damage checkpoint protein 1 (MDC1)-Ring Finger Protein-8 (RNF8) protein complex physically protects ataxia telangiectasia-mutated Ser/Thr kinase (ATM)-phosphorylated MDC1 from caspase-3-dependent proteolytic cleavage in bridging integrator 1 (BIN1)-deficient cancer cells in the presence of cisplatin
Since the formation of the ATM-dependent MDC1-RNF8 complex is associated with cancer-cell survival in the presence of cisplatin, we propose that ATM inactivation by an ATM inhibitor, which destabilizes the MDC1-RNF8 interaction, would be a possible therapeutic option to restore cisplatin sensitivity even in BIN1-deficient cancer cells (Figure 4F)

Summary

Introduction

Rosenberg et al discovered the potent anti-cell division property of cis-diammine dichloro platinum (cisplatin or CDDP) first in Escherichia coli and in tumor cells in the 1960s [1,2]. Inspired by this epoch-making finding, Einhorn et al reported a remarkable therapeutic efficacy of cisplatin in patients with refractory testicular cancer in the 1970s [3,4]. Cisplatin frequently forms platinum-DNA adducts to interfere with DNA replication, transcription, and repair. The robust increase in DSBs could be the most likely cause of cisplatin-induced catastrophic cell death in cancer. Because most cancer cells are initially susceptible to cisplatin, we assume that a cell deathpromoting mechanism caused by DSBs could be impaired in advanced cancer cells

Methods

Results

Discussion

Conclusion