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

Cancer Cell. 2018 Aug 13;34(2):315-330.e7. doi: 10.1016/j.ccell.2018.06.012. Epub 2018 Jul 19.

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.

Keywords: MAPK signaling; cisplatin resistance; dual-kinase inhibitor; lestaurtinib; microtubule-associated serine/threonine kinase 1; platinum-based cancer therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cisplatin / pharmacology*
  • Drug Resistance, Neoplasm
  • Enzyme Activation
  • Female
  • Humans
  • MAP Kinase Kinase 1 / physiology*
  • Mice
  • Microtubule-Associated Proteins / physiology*
  • Protein-Serine-Threonine Kinases / physiology*
  • Proto-Oncogene Proteins c-raf / physiology*

Substances

  • Antineoplastic Agents
  • Microtubule-Associated Proteins
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-raf
  • Raf1 protein, human
  • MAP Kinase Kinase 1
  • MAP2K1 protein, human
  • Cisplatin