Merlin deficiency predicts FAK inhibitor sensitivity: a synthetic lethal relationship

Our plain-English summary of Merlin deficiency predicts FAK inhibitor sensitivity: a synthetic lethal relationship, by I.M. Shapiro, V.N. Kolev, C.M. Vidal, et al (Science Translational Medicine, 2014).

The study

• Authors: I.M. Shapiro, V.N. Kolev, C.M. Vidal, Y. Kadariya, J.E. Ring, Q. Wright, D.T. Weaver, C. Menges, M. Padval, A.I. McClatchey, Q. Xu, J.R. Testa, J.A. Pachter
• Journal: Science Translational Medicine
• Published: 2014;6(237):237ra68
• Cited by: 216 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The goal of targeted therapy is to match a selective drug with a genetic lesion that predicts for drug sensitivity. In a diverse panel of cancer cell lines, we found that the cells most sensitive to focal adhesion kinase (FAK) inhibition lack expression of the neurofibromatosis type 2 (NF2) tumor suppressor gene product, Merlin. Merlin expression is often lost in malignant pleural mesothelioma (MPM), an asbestos-induced aggressive cancer with limited treatment options. Our data demonstrate that low Merlin expression predicts for increased sensitivity of MPM cells to a FAK inhibitor, VS-4718, in vitro and in tumor xenograft models. Disruption of MPM cell-cell or cell-extracellular matrix (ECM) contacts with blocking antibodies suggests that weak cell-cell adhesions in Merlin-negative MPM cells underlie their greater dependence on cell-ECM-induced FAK signaling. This provides one explanation of why Merlin-negative cells are vulnerable to FAK inhibitor treatment. Furthermore, we validated aldehyde dehydrogenase as a marker of cancer stem cells (CSCs) in MPM, a cell population thought to mediate tumor relapse after chemotherapy. Whereas pemetrexed and cisplatin, standard-of-care agents for MPM, enrich for CSCs, FAK inhibitor treatment preferentially eliminates these cells. These preclinical results provide the rationale for a clinical trial in MPM patients using a FAK inhibitor as a single agent after first-line chemotherapy. With this design, the FAK inhibitor could potentially induce a more durable clinical response through reduction of CSCs along with a strong antitumor effect. Furthermore, our data suggest that patients with Merlin-negative tumors may especially benefit from FAK inhibitor treatment.

Copyright © 2014, American Association for the Advancement of Science.

In plain English

This laboratory study of cancer cells and mice did not study people or asbestos exposure. The authors tested VS-4718, an experimental drug blocking the enzyme focal adhesion kinase (FAK). They used 47 human cancer cell lines and mouse tumor models, focusing on malignant pleural mesothelioma and cells lacking the protein Merlin. Seven of the 10 most sensitive cell lines lacked Merlin. In mesothelioma cell lines, the concentration giving half the maximum effect averaged 0.3 micromolar in Merlin-negative lines and about 3.5 in Merlin-positive lines. In mice carrying tumors grown from human mesothelioma samples, a Merlin-negative tumor showed 56% growth inhibition on day 35 compared with untreated controls. Merlin-positive tumors ended 23% smaller than untreated ones, and their weights did not differ significantly. Given after cisplatin and pemetrexed, the drug gave 77% growth inhibition by day 46 versus chemotherapy alone. In cell experiments, the drug lowered the proportion of cells carrying the authors' cancer stem cell marker, while standard chemotherapy drugs raised that proportion. The authors concluded that their data suggest a "synthetic lethal" relationship between Merlin loss and FAK inhibitor sensitivity.

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: Preclinical laboratory study: experiments in human and mouse cancer cell lines and in mouse tumor (xenograft) models, including patient-derived mesothelioma xenografts
• Who was studied: The study used no human subjects and gives no dates. It covered 47 human cancer cell lines of diverse tumor types (renal, thyroid, ovarian and breast carcinomas, non-small cell lung cancer, melanoma, mesothelioma) and a panel of 10 mesothelioma cell lines. It also used mice bearing breast cancer xenografts, MM87 murine mesothelioma tumors, and human malignant pleural mesothelioma patient-derived xenografts.
• Exposure: No asbestos exposure was studied. The treatment tested was the FAK inhibitor VS-4718, given to mice orally twice daily at 25 to 100 mg/kg. It was compared with, or followed, standard chemotherapy (cisplatin and pemetrexed; in cell experiments also vinorelbine and gemcitabine).
• Main results:
  • In the 47-cell-line panel, 7 of the 10 cell lines most sensitive to VS-4718 lacked Merlin protein.
  • Among the 37 less sensitive cell lines, 92% expressed high Merlin levels and 8% showed loss of Merlin.
  • In mesothelioma cell lines grown in 3D culture, the average EC50 (the concentration giving half-maximal effect) was about 3.5 micromolar for Merlin-positive lines and 0.3 micromolar for Merlin-negative lines.
  • Adding Merlin back into Merlin-negative MM87 mesothelioma cells raised the EC50 by about threefold, meaning the cells became less sensitive to the drug.
  • In a Merlin-negative MM87 intraperitoneal mouse model, tumors treated at 25 mg/kg averaged about 100 mm3, compared with about 500 mm3 in controls.
  • In the same model, a measurable tumor was seen in only 1 of 10 animals treated at 50 or 75 mg/kg.
  • In the Merlin-negative human mesothelioma patient-derived xenograft, VS-4718 at 50 mg/kg gave 56% tumor growth inhibition on day 35 compared with vehicle-treated controls (P = 0.0089).
  • In the Merlin-positive patient-derived xenograft, treated tumors averaged only 23% smaller than controls on day 42.
  • In the Merlin-positive patient-derived xenograft, tumor weights on day 42 were not significantly different from controls (P = 0.19).
  • In the Merlin-negative patient-derived xenograft, tumors regrew after cisplatin plus pemetrexed stopped.
  • VS-4718 given alone after the cisplatin/pemetrexed course gave 77% tumor growth inhibition by day 46 compared with the cisplatin/pemetrexed arm (P = 0.035).
  • The authors validated Aldefluor as a cancer stem cell marker. Aldefluor-positive MM87 cells had about 35-fold higher tumor-initiating potential than Aldefluor-negative cells (P less than 0.0001).
  • In Merlin-negative H2052 mesothelioma cells, VS-4718 reduced the percentage of Aldefluor-positive cells. Pemetrexed, cisplatin, vinorelbine and gemcitabine instead enriched the Aldefluor-positive subpopulation.
  • In Merlin-positive MSTO-211H cells, blocking cell-cell contacts with an N-cadherin antibody increased the drug's potency about 60-fold.
  • In mice with Merlin-positive MDA-MB-468 breast cancer xenografts, final tumor weights in treated groups were reduced only by about 30%.
• The authors' conclusion: The authors concluded that their data suggest a synthetic lethal relationship between Merlin loss and FAK inhibitor sensitivity. They described this as an attractive strategy for clinical testing of FAK inhibitors in patients with malignant pleural mesothelioma.
• Limitations the authors state:
  • The authors stated that further studies are needed to extend the Merlin and FAK inhibitor relationship to tumor types beyond the mesothelioma tumors studied.
  • Some ovarian cancer cell lines were sensitive despite normal Merlin. The authors took this to mean that other predictive markers and mechanisms remain to be found.

Topics

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

Medical terms in this study, explained in our Lexicon: Merlin, Targeted Therapy, Tumor Suppressor Gene, Pleural Mesothelioma, STEM, Chemotherapy, Pemetrexed (Alimta), Cisplatin.

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• Combination of a p53-activating CP-31398 and an MDM2 or a FAK inhibitor produces growth suppressive effects in mesothelioma with wild-type p53 genotype — B. Zhong, M. Shingyoji, et al. (2020)
• The Role of E-Cadherin and microRNA on FAK Inhibitor Response in Malignant Pleural Mesothelioma (MPM) — M.L. Yuen, L. Zhuang, et al. (2021)
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