Inhibiting crosstalk between MET signaling and mitochondrial dynamics and morphology: a novel therapeutic approach for lung cancer and mesothelioma

Our plain-English summary of Inhibiting crosstalk between MET signaling and mitochondrial dynamics and morphology: a novel therapeutic approach for lung cancer and mesothelioma, by J. Wang, T. Mirzapoiazova, Y.H. Carol Tan, et al (Cancer Biology & Therapy, 2018).

The study

• Authors: J. Wang, T. Mirzapoiazova, Y.H. Carol Tan, K.M. Pang, A. Pozhitkov, Y. Wang, Y. Wang, B. Mambetsariev, E. Wang, M.W. Nasser, S.K. Batra, D. Raz, K. Reckamp, P. Kulkarni, Y. Zheng, R. Salgia
• Journal: Cancer Biology & Therapy
• Published: 2018;19(11):1023-1032
• Cited by: 17 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The receptor tyrosine kinase MET is frequently involved in malignant transformation and inhibiting its activity in MET-dependent cancers is associated with improved clinical outcomes. Emerging evidence also suggests that mitochondria play an essential role in tumorigenesis and Dynamin Related Protein (DRP1), a key component of the mitochondrial fission machinery, has emerged as an attractive therapeutic target. Here, we report that inhibiting MET activity with the tyrosine kinase inhibitor MGCD516 attenuates viability, migration, and invasion of non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM) cell lines in vitro, and significantly retards tumor growth in vivo. Interestingly, MGCD516 treatment also results in altered mitochondrial morphology in these cell lines. Furthermore, inhibiting MET pharmacologically or knocking down its expression using siRNA, decreases DRP1 activity alluding to possible crosstalk between them in these two cancers. Consistently, a combination of MGCD516 and mdivi-1, a quinazolinone reported to inhibit mitochondrial fission, is more effective in attenuating proliferation of NSCLC and MPM cell lines than either drug alone. Considered together, the present study has uncovered a novel mechanism underlying mitochondrial regulation by MET that involves crosstalk with DRP1, and suggests that a combination therapy targeting both MET and DRP1 could be a novel strategy for NSCLC and MPM.

In plain English

This was a laboratory study of cancer cell lines and mice. It did not study asbestos exposure or patients. The authors tested MGCD516, a drug that blocks a protein called MET, on two non-small cell lung cancer (NSCLC) cell lines (A549, H1993) and two malignant pleural mesothelioma (MPM) cell lines (H2373, H2461). Cell lines with more MET were more sensitive. The drug dose that halved viability (IC50) was 0.8μM for H1993 versus 4.7μM for A549, and 4.4μM for H2373 versus 6.0μM for H2461. In H1993 and H2373 cells the drug reduced invasion and delayed wound healing. It also lowered activity of DRP1, a protein involved in dividing mitochondria, and made mitochondria longer. Knocking down MET with siRNA had similar effects. In mice carrying H1993 tumors (5 per group), 20 mg/kg for 25 days inhibited tumor growth compared with vehicle-treated mice. In the four cell lines, mdivi-1 alone was relatively ineffective, but combined with MGCD516 it reduced cell viability more than either drug alone. The authors concluded that targeting both MET and DRP1 could be a novel strategy for NSCLC and MPM. They noted that mdivi-1's specificity remains equivocal.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: experiments on cancer cell lines (in vitro) plus a mouse xenograft experiment
• Who was studied: Cell lines: NSCLC lines A549 and H1993 and MPM lines H2373 and H2461, with control lines BEAS-2B (non-tumorigenic lung epithelial) and MeT-5A (mesothelial control). Also female athymic nude mice injected with H1993 cells, 5 mice per group.
• Exposure: No asbestos exposure was studied. The exposures were the MET inhibitor MGCD516 (2μM in many cell experiments; 20 mg/kg daily by oral gavage for 25 days in mice), MET-specific siRNA, and mdivi-1 alone and in combination with MGCD516.
• Main results:
  • MET protein expression was higher in the NSCLC and MPM cell lines than in their respective control cell lines.
  • In NSCLC lines, H1993 (higher MET) was sensitive to MGCD516 (IC50 0.8μM; printed as 'H19193', an apparent typo for H1993). A549 (lower MET) was fairly resistant (IC50 4.7μM).
  • In MPM lines, H2373 (higher MET) was more sensitive to MGCD516 (IC50 4.4μM) than H2461 (IC50 6.0μM, lower MET).
  • MGCD516 (2μM, 24 h) attenuated invasiveness compared with DMSO control. The figures reported were 17.6% (p = 0.0002) for H1993 cells and 35.0% (p = 0.0088) for H2373 cells; the text does not define what these percentages measure. The drug also delayed wound healing in both lines.
  • In H1993 and H2373 cells, MGCD516 lowered phosphorylated MET, Erk1/2 and DRP1 and reduced total Fis1. Mitochondria became more elongated and were significantly longer than in DMSO-treated controls.
  • Knocking down MET with MET-specific siRNA in H1993 and H2373 cells also lowered DRP1 and made mitochondria significantly longer than with control siRNA.
  • In mice with H1993 xenograft tumors, MGCD516 inhibited tumor growth compared with vehicle-treated controls and reduced phospho-Met and phospho-DRP1 in tumor tissue. No numerical tumor sizes were given in the text.
  • In cell viability tests on the H1993, A549, H2373 and H2461 cell lines, mdivi-1 alone was relatively ineffective, while the combination with MGCD516 was more effective than either drug alone. The combination was reported only in these cell-line experiments.
• The authors' conclusion: The authors concluded that they had found a mechanism of crosstalk between MET and the mitochondrial fission protein DRP1. They suggested that combination therapy targeting both MET and DRP1 could be a novel strategy for NSCLC and MPM.
• Limitations the authors state:
  • The authors stated that the specificity and mode of action of mdivi-1, the DRP1-inhibiting drug used, remain uncertain.
  • The authors stated that the exact role of MET-phosphorylated DRP1 in cancer remains unknown.
  • The authors noted that MGCD516 also inhibits other receptor tyrosine kinases, so its effects could be indirect. They used MET siRNA to address this.

Topics

Medical terms in this study, explained in our Lexicon: Lung Cancer, Mesothelioma, Malignant Transformation, Carcinogenesis, Tyrosine Kinase Inhibitor, Non-Small Cell Lung Cancer, Pleural Mesothelioma.

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