title: Mitochondrial-Targeting MET Kinase Inhibitor Kills Erlotinib-Resistant Lung Cancer Cells.
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.
authors: Department of Pharmacy, National University of Singapore , 18 Science Drive 4, Singapore 117543.
authors: Tianming
authors: T
authors: Yang
authors: 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.
authors: Wai Har
authors: WH
authors: Ng
authors: Department of Pharmacy, National University of Singapore , 18 Science Drive 4, Singapore 117543.
authors: Huan
authors: H
authors: Chen
authors: Department of Pharmacy, National University of Singapore , 18 Science Drive 4, Singapore 117543.
authors: Kamon
authors: K
authors: Chomchopbun
authors: 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.
authors: The Hung
authors: TH
authors: Huynh
authors: Department of Pharmacy, National University of Singapore , 18 Science Drive 4, Singapore 117543.
authors: Mei Lin
authors: ML
authors: Go
authors: 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.
authors: Oi Lian
authors: OL
authors: Kon
keywords: MET kinase; Mitochondrial targeting; PHA665752; drug resistance; nonsmall cell lung cancer; triphenylphosphonium conjugate