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.

Metabolic Remodelling: An Accomplice for New Therapeutic Strategies to Fight Lung Cancer

“…NSCLC cells resistant to EGFR TKIs, gefitinib and erlotinib, were shown to exhibit elevated OXPHOS accompanied by elevated glycolysis and activity in TCA cycle [182]. In A549 NSCLC cell line, erlotinib drove ROS-mediated apoptosis via activation of the c-Jun N-terminal kinase (JNK) pathway, leading ultimately to EGFR inhibition [183].…”

Essential roles of mitochondrial and heme function in lung cancer bioenergetics and tumorigenesis

“…Recent studies have shown that several cancers have adapted and rewired their cells to rely more on mitochondrial OXPHOS for drug resistance [ 93 – 98 ]. Cancer cells have shifted gears to elevated OXPHOS through several different mechanisms ranging from gene upregulations to ectopic protein expressions [ 93 , 99 ].…”

“…Oligomycin, an inhibitor of OXPHOS, abolished the tumor initiating abilities of CSCs, thereby implicating the role of OXPHOS in initiation of SCLC [ 100 ]. Similarly, NSCLC cells that are resistant to EGFR tyrosine kinase inhibitors, gefitinib and erlotinib, were shown to exhibit elevated OXPHOS accompanied by elevated glycolysis and activity in TCA cycle [ 99 ]. This metabolic shift to increased OXPHOS was found to be a result of MET (mesenchymal–epithelial transition factor) proto-oncogene expression in the mitochondrial membrane in addition to plasma membrane.…”

“…This metabolic shift to increased OXPHOS was found to be a result of MET (mesenchymal–epithelial transition factor) proto-oncogene expression in the mitochondrial membrane in addition to plasma membrane. Pharmacological inhibition of MET resulted in cytotoxicity and apoptosis [ 99 ]. Interestingly, cancer cells rewire metabolism by altering the localization of proteins and expressing them ectopically in mitochondria [ 93 , 99 ].…”

“…Pharmacological inhibition of MET resulted in cytotoxicity and apoptosis [ 99 ]. Interestingly, cancer cells rewire metabolism by altering the localization of proteins and expressing them ectopically in mitochondria [ 93 , 99 ]. 3-Oxoacid CoA-transferase 1 (OXAT1) and acetyl-CoA acetyltransferase 1 (ACAT1) are proteins localized in mitochondria and are involved in utilization of ketone bodies to aid in tumor growth and metastasis.…”