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New Synthetic Lethality Re-Sensitizing Platinum-Refractory Cancer Cells to Cisplatin In Vitro: The Rationale to

Watson P Folk1,2, Alpana Kumari1,2, Tetsushi Iwasaki1,2,3

  • 1Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.

International Journal of Molecular Sciences
|December 24, 2021
PubMed

Insights

Cancer cells gain cisplatin resistance through BIN1 deficits, driven by MYC, PARP1, and ATM. Inhibiting PARP1 and ATM re-sensitizes platinum-refractory cancers by restoring BIN1 function.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • The tumor suppressor BIN1 normally inhibits MYC, PARP1, and ATM, crucial for cancer cell survival.
  • BIN1 deficiency is linked to cisplatin resistance, but the underlying mechanisms and triggers are unclear.
  • Understanding BIN1's role is vital for overcoming chemotherapy resistance in cancers.

Purpose of the Study:

  • To elucidate how MYC, PARP1, and ATM contribute to cisplatin resistance when BIN1 is deficient.
  • To investigate the role of DNA damage response (DDR) pathways in BIN1-mediated chemoresistance.
  • To identify potential therapeutic strategies for restoring cisplatin sensitivity in resistant cancers.

Main Methods:

  • Investigated the effect of BIN1 depletion on cisplatin sensitivity in cancer cells.
  • Analyzed the impact of BIN1 deficiency on ATM-mediated phosphorylation of DDR proteins like MDC1.
  • Examined the role of RNF8 in protecting MDC1 from degradation and its contribution to chemoresistance.
  • Assessed the interplay between MYC, PARP1, and BIN1 promoter activity under cisplatin treatment.
  • Evaluated the efficacy of combined PARP1 and ATM inhibition in restoring cisplatin sensitivity.

Main Results:

  • BIN1 depletion conferred cisplatin resistance, independent of TP53 status.
  • BIN1 deficiency enhanced ATM's phosphorylation of MDC1, facilitating RNF8 binding and protecting MDC1 from cleavage, thus hindering apoptosis.
  • Chronic cisplatin exposure mimicked BIN1 loss, inducing RNF8-dependent resistance.
  • PARP1-activated MYC repressed BIN1 expression; PARP1 inhibition reversed this suppression and restored sensitivity.
  • Simultaneous inhibition of PARP1 and ATM re-established cisplatin sensitivity in platinum-refractory cells.

Conclusions:

  • Coordinated actions of MYC, PARP1, and ATM promote cisplatin resistance by enabling BIN1 deficits.
  • The BIN1-ATM-MDC1-RNF8 axis is a key mechanism by which cancer cells evade cisplatin-induced apoptosis.
  • Targeting PARP1 and ATM simultaneously offers a novel, BRCAness-independent synthetic lethal strategy to overcome platinum resistance in diverse cancers.
Keywords:
ATMBIN1MDC1-RNF8 complexMYCPARP1apoptosiscisplatin resistance

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