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Published on: May 27, 2021
Merlin deficiency predicts FAK inhibitor sensitivity: a synthetic lethal relationship
Irina M Shapiro1, Vihren N Kolev1, Christian M Vidal1
1Verastem Inc., Cambridge, MA 02142, USA.
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.
Insights
Malignant pleural mesothelioma cells lacking Merlin expression are sensitive to FAK inhibitors. This targeted therapy may reduce cancer stem cells, offering a new treatment strategy for this aggressive cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Targeted cancer therapy aims to pair drugs with genetic markers predicting sensitivity.
- Neurofibromatosis type 2 (NF2) tumor suppressor gene product, Merlin, is often lost in malignant pleural mesothelioma (MPM).
- Loss of Merlin expression in MPM correlates with sensitivity to focal adhesion kinase (FAK) inhibition.
Purpose of the Study:
- To investigate the role of Merlin expression in MPM sensitivity to FAK inhibitors.
- To explore FAK inhibition as a targeted therapy for MPM, particularly in Merlin-negative tumors.
- To assess the effect of FAK inhibition on cancer stem cells (CSCs) in MPM.
Main Methods:
- Screening a diverse panel of cancer cell lines for sensitivity to FAK inhibition.
- Evaluating the efficacy of FAK inhibitor VS-4718 in Merlin-negative MPM cell lines and tumor xenografts.
- Assessing the impact of FAK inhibition on CSCs using aldehyde dehydrogenase as a marker.
- Investigating the role of cell-cell and cell-extracellular matrix (ECM) interactions in FAK signaling.
Main Results:
- Cells with low or absent Merlin expression demonstrated increased sensitivity to FAK inhibition.
- MPM cells lacking Merlin showed a greater dependence on FAK signaling for survival.
- FAK inhibitor treatment preferentially eliminated CSCs in MPM, unlike standard chemotherapies.
- Preclinical data support the use of FAK inhibitors in MPM, especially in Merlin-negative cases.
Conclusions:
- Low Merlin expression is a predictive biomarker for FAK inhibitor sensitivity in MPM.
- FAK inhibition offers a promising targeted therapy for MPM by reducing both tumor bulk and CSCs.
- Targeted FAK inhibition presents a potential strategy for more durable clinical responses in MPM patients, particularly those with Merlin-negative tumors.
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