MAST1 Drives Cisplatin Resistance in Human Cancers by Rewiring cRaf-Independent MEK Activation

Lingtao Jin, Jaemoo Chun, Chaoyun Pan, Dan Li, Ruiting Lin, Gina N. Alesi, Xu Wang, Hee Bum Kang, Lina Song, Dongsheng Wang, Guojing Zhang, Jun Fan, Titus J. Boggon, Lu Zhou, Jeanne Kowalski, Cheng Kui Qu, Conor E. Steuer, Georgia Z. Chen, Nabil F. Saba, Lawrence H. BoiseTaofeek K. Owonikoko, Fadlo R. Khuri, Kelly R. Magliocca, Dong M. Shin, Sagar Lonial, Sumin Kang

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

Platinum-based chemotherapeutics represent a mainstay of cancer therapy, but resistance limits their curative potential. Through a kinome RNAi screen, we identified microtubule-associated serine/threonine kinase 1 (MAST1) as a main driver of cisplatin resistance in human cancers. Mechanistically, cisplatin but no other DNA-damaging agents inhibit the MAPK pathway by dissociating cRaf from MEK1, while MAST1 replaces cRaf to reactivate the MAPK pathway in a cRaf-independent manner. We show clinical evidence that expression of MAST1, both initial and cisplatin-induced, contributes to platinum resistance and worse clinical outcome. Targeting MAST1 with lestaurtinib, a recently identified MAST1 inhibitor, restores cisplatin sensitivity, leading to the synergistic attenuation of cancer cell proliferation and tumor growth in human cancer cells and patient-derived xenograft models. Jin et al. show that cisplatin dissociates cRaf from MEK1 to inhibit the MAPK pathway and identify MAST1 as a main cisplatin resistance driver that replaces cRaf to reactivate the MAPK pathway. They further show that inhibition of MAST1 by the multi-kinase inhibitor lestaurtinib restores cisplatin sensitivity.

Original languageEnglish (US)
Pages (from-to)315-330.e7
JournalCancer Cell
Volume34
Issue number2
DOIs
StatePublished - Aug 13 2018
Externally publishedYes

Keywords

  • MAPK signaling
  • cisplatin resistance
  • dual-kinase inhibitor
  • lestaurtinib
  • microtubule-associated serine/threonine kinase 1
  • platinum-based cancer therapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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