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Cancer Biol Ther. 2014 Jun 1;15(6):721-34. doi: 10.4161/cbt.28409. Epub 2014 Mar 11.

A novel lead compound CM-118: antitumor activity and new insight into the molecular mechanism and combination therapy strategy in c-Met- and ALK-dependent cancers.

Author information

  • 1Department of Pharmacology; Fudan University School of Pharmacy; Shanghai, PR China; Department of Nuclear Medicine; Zhongshan Hospital; Fudan University; Shanghai, PR China.
  • 2School of Pharmacy; Shanghai Jiaotong University; Shanghai, PR China.
  • 3Department of Pharmacology; Fudan University School of Pharmacy; Shanghai, PR China.
  • 4Sundia MediTech; Shanghai, PR China.
  • 5Xcovery Inc.; West Palm Beach, FL USA.

Abstract

The anaplastic lymphoma kinase (ALK) and the c-Met receptor tyrosine kinase play essential roles in the pathogenesis in multiple human cancers and present emerging targets for cancer treatment. Here, we describe CM-118, a novel lead compound displaying low nanomolar biochemical potency against both ALK and c-Met with selectivity over>90 human kinases. CM-118 potently abrogated hepatocyte growth factor (HGF)-induced c-Met phosphorylation and cell migration, phosphorylation of ALK, EML4-ALK, and ALK resistance mutants in transfected cells. CM-118 inhibited proliferation and/or induced apoptosis in multiple c-Met- and ALK-addicted cancer lines with dose response profile correlating target blockade. We show that the CM-118-induced apoptosis in c-Met-amplified H1993 NSCLC cells involved a rapid suppression of c-Met activity and c-Met-to-EGFR cross-talk, and was profoundly potentiated by EGFR inhibitors as shown by the increased levels of apoptotic proteins cleaved-PARP and Bim as well as reduction of the survival protein Mcl-1. Bim-knockdown or Mcl-1 overexpression each significantly attenuated apoptosis. We also revealed a key role by mTOR in mediating CM-118 action against the EML4-ALK-dependent NSCLC cells. Abrogation of EML4-ALK in H2228 cells profoundly reduced signaling capacity of the rapamycin-sensitive mTOR pathway leading to G 1 cell cycle arrest and mitochondrial hyperpolarization, a metabolic perturbation linked to mTOR inhibition. Depletion of mTOR or mTORC1 inhibited H2228 cell growth, and mTOR inhibitors potentiated CM-118's antitumor activity in vitro and in vivo. Oral administration of CM-118 at a wide range of well tolerated dosages diminished c-Met- and ALK phosphorylation in vivo, and caused tumor regression or growth inhibition in multiple c-Met- and ALK-dependent tumor xenografts in mice. CM-118 exhibits favorable pharmacokinetic and drug metabolism properties hence presents a candidate for clinical evaluation.

KEYWORDS:

ALK; EGFR; c-Met; combination therapy; mTOR; targeted cancer therapy

Comment in

  • Met in lung cancer. [Cancer Biol Ther. 2014]
PMID:
24618813
[PubMed - in process]
PMCID:
PMC4049788
[Available on 2015/6/1]
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