Combined inhibition of MET and EGFR suppresses proliferation of malignant mesothelioma cells

Our plain-English summary of Combined inhibition of MET and EGFR suppresses proliferation of malignant mesothelioma cells, by K. Kawaguchi, H. Murakami, T. Taniguchi, et al (Carcinogenesis, 2009).

The study

• Authors: K. Kawaguchi, H. Murakami, T. Taniguchi, M. Fujii, S. Kawata, T. Fukui, Y. Kondo, H. Osada, N. Usami, K. Yokoi, Y. Ueda, Y. Yatabe, M. Ito, Y. Horio, T. Hida, Y. Sekido
• Journal: Carcinogenesis
• Published: 2009;30(7):1097-105
• Cited by: 73 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive neoplasm associated with asbestos exposure. Although expression and activation of receptor tyrosine kinases (RTKs), including MET, have been reported in most MPM, specific RTK inhibitors showed less than the expected response in MPM cells. To determine whether the lack of response of MET inhibitors was due to cooperation with other RTKs, we determined activation status of MET and other RTKs, including epidermal growth factor receptor (EGFR) family of 20 MPM cell lines, and tested whether dual RTK inhibition is an effective therapeutic strategy. We detected MET upregulation and phosphorylation (thus indicating activation) in 14 (70%) and 13 (65%) cell lines, but treatment with MET-specific inhibitors showed weak or modest effect of suppression in most of the cell lines. Phospho-RTK array analysis revealed that MET was simultaneously activated with other RTKs, including EGFR, ErbB2, ErbB3 and platelet-derived growth factor receptor-beta. Combination of MET and EGFR inhibitors triggered stronger inhibition on cell proliferation and invasion of MPM cells than that of each in vitro. These results indicated that coactivation of RTKs was essential in mesothelioma cell proliferation and/or survival, thus suggesting that simultaneous inhibition of RTKs may be a more effective strategy for the development of molecular target therapy for MPM.

In plain English

This was a laboratory study of mesothelioma cells. It did not test treatments in patients or study asbestos exposure, but it examined patient tumor tissue. The authors examined 20 malignant pleural mesothelioma cell lines, 14 established in their own laboratory from Japanese patients. They also stained 35 malignant mesothelioma tumor specimens: 23 pleural, 6 peritoneal and 6 from other sites. MET, a growth-signal receptor, was raised in 15 of 20 lines at the RNA level and 14 at the protein level, and active in 13. Of 35 tumor specimens, 28 stained positive for MET. Sequencing MET in the 20 cell lines found no protein-changing mutations. Blocking MET alone, by gene silencing or the drug SU11274, slowed growth only modestly; with SU11274, 11 of 13 lines were relatively resistant. Another receptor, EGFR, was active in every mesothelioma line tested on a receptor array. In the seven lines tested, combining MET and EGFR blockers suppressed growth more than either alone, and the combination reduced migration and invasion in three lines. The authors suggested that blocking several receptors may help develop more effective targeted therapy.

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 (in vitro) study of mesothelioma cell lines, with staining of tumor tissue specimens
• Who was studied: The study used 20 malignant pleural mesothelioma cell lines. Fourteen were Japanese lines established in the authors' laboratory; the others came from the American Type Culture Collection or were a gift. It also used one immortalized mesothelial cell line (MeT-5A), two primary cultures of normal mesothelial cells, and 35 malignant mesothelioma specimens (23 pleural, 6 peritoneal, 2 lung, 1 heart, 1 mesentery, 1 bone, 1 kidney). Of the specimens, 16 were obtained from patients at Japanese hospitals and 19 came from a commercial US tissue array.
• Exposure: No asbestos exposure was studied. The cells were treated with receptor-blocking drugs, alone and in combination: SU11274 and PHA665752 for MET, PD153035 for EGFR, AG1295 for PDGFR, and SU5402 for fibroblast growth factor receptor. MET was also silenced with shRNA, and the pathway blockers LY294002 and PD98059 were used.
• Main results:
  • Among the 20 cell lines, 15 (75%) showed raised MET at the RNA level and 14 (70%) at the protein level.
  • Activated (phosphorylated) MET was detected in 13 cell lines.
  • Of 35 mesothelioma specimens, 28 (80%) stained positive for MET.
  • MET was sequenced in the 20 cell lines. Sequencing found only common gene variants (single-nucleotide polymorphisms), with no mutation that changes the protein.
  • Silencing MET produced weak growth inhibition in NCI-H290, moderate inhibition in Y-MESO-29, and none in NCI-H2373.
  • With the MET blocker SU11274 at 5 micromolar, two of 13 cell lines (NCI-H290 and Y-MESO-29) showed 30% growth suppression compared with controls. The other 11 lines and MeT-5A were relatively resistant.
  • On the receptor array of 15 mesothelioma cell lines, EGFR was activated in all lines tested. On average, 6.5 of 42 receptors were activated per line.
  • The EGFR blocker PD153035 alone moderately suppressed growth in 3 of 11 mesothelioma cell lines. The other eight lines and MeT-5A showed weak suppression.
  • Combined MET and EGFR blockade suppressed growth more than either drug alone in NCI-H2373 and NCI-H290. It did the same in five further cell lines, for which the data were not shown.
  • Combined MET and EGFR blockade suppressed cell migration and invasion in three mesothelioma cell lines.
  • The PI3-K pathway blocker LY294002 inhibited growth in all five mesothelioma cell lines tested.
• The authors' conclusion: The authors concluded that activation of multiple receptor tyrosine kinases is critical for mesothelioma cell growth and/or survival. They suggested that inhibiting several of these receptors may help develop more effective targeted therapy for patients with malignant pleural mesothelioma in the future.
• Limitations the authors state:
  • In one pair of a tumor and the cell line grown from it, MET levels did not match. The authors suggested cell selection during culture as one possible reason.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: EGFR, Mesothelioma, Pleural Mesothelioma, Neoplasm, Asbestos Exposure, Platelet-Derived Growth Factor (PDGF).

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