2. Academic Validation
  3. Mitochondrial-Targeting MET Kinase Inhibitor Kills Erlotinib-Resistant Lung Cancer Cells

Mitochondrial-Targeting MET Kinase Inhibitor Kills Erlotinib-Resistant Lung Cancer Cells

  • ACS Med Chem Lett. 2016 Jun 23;7(8):807-12. doi: 10.1021/acsmedchemlett.6b00223.
Tianming Yang 1,  Wai Har Ng 2,  Huan Chen 1,  Kamon Chomchopbun 1,  The Hung Huynh 2,  Mei Lin Go 1,  Oi Lian Kon 3
Affiliations

Affiliations

  • 1 Department of Pharmacy, National University of Singapore , 18 Science Drive 4, Singapore 117543.
  • 2 Division of Medical Sciences, Laboratory of Applied Human Genetics and Division of Cellular & Molecular Research, Laboratory of Molecular Endocrinology, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore , 11 Hospital Drive, Singapore 169610.
  • 3 Division of Medical Sciences, Laboratory of Applied Human Genetics and Division of Cellular & Molecular Research, Laboratory of Molecular Endocrinology, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore 169610; Department of Biochemistry, National University of Singapore, 8 Medical Drive, Singapore 117596.
PMID: 27563407 DOI: 10.1021/acsmedchemlett.6b00223
Abstract

Lung Cancer cells harboring activating EGFR mutations acquire resistance to EGFR tyrosine kinase inhibitors (TKIs) by activating several bypass mechanisms, including MET amplification and overexpression. We show that a significant proportion of activated MET protein in EGFR TKI-resistant HCC827 lung Cancer cells resides within the mitochondria. Targeting the total complement of MET in the plasma membrane and mitochondria should render these cells more susceptible to cell death and hence provide a means of circumventing drug resistance. Herein, the mitochondrial targeting triphenylphosphonium (TPP) moiety was introduced to the selective MET kinase inhibitor PHA665752. The resulting TPP analogue rapidly localized to the mitochondria of MET-overexpressing erlotinib-resistant HCC827 cells, partially suppressed the phosphorylation (Y1234/Y1235) of MET in the mitochondrial inner membrane and was as cytotoxic and apoptogenic as the parent compound. These findings provide support for the targeting of mitochondrial MET with a TPP-TKI conjugate as a means of restoring responsiveness to chemotherapy.

Keywords

MET kinase; Mitochondrial targeting; PHA665752; drug resistance; nonsmall cell lung cancer; triphenylphosphonium conjugate.

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