FAK Inhibitor Kills Mesothelioma Cells

An experimental oral focal adhesion kinase (FAK) inhibitor called VS-4718 may deliver a one-two punch against malignant pleural mesothelioma (MPM), an aggressive lung cancer associated with asbestos exposure. In preclinical experiments, the drug killed tumor cells as well as cancer stem cells, which often evade chemotherapy and may lead to disease recurrence.

Combination chemotherapy has shown some benefit in the treatment of MPM, but it is limited: The median overall survival is between 6 and 18 months.

“It's an aggressive disease with an unmet medical need,” says Jonathan Pachter, PhD, senior author of an article on VS-4718 published in May in Science Translational Medicine, and head of research for Verastem, the Boston, MA–based biopharmaceutical company developing VS-4718. Pachter notes that if MPM returns after first-line chemotherapy, patients have no approved treatment options.

The new study suggests a promising extension of front-line therapy: “If you treat mesothelioma with a FAK inhibitor immediately following front-line chemotherapy, you could potentially prevent the tumor from recurring and meaningfully increase survival,” says Pachter. Enrollment is now open for a phase I clinical trial of the drug.

Cancer researchers have been looking for ways to inhibit FAK because elevated levels of the protein have been observed in a spectrum of cancer types. It also plays a role in many steps of tumorigenesis, and FAK inhibitors have shown promise for controlling various cancers. However, researchers have made little progress in identifying biomarkers that accurately predict the patient populations most likely to respond to the treatment.

Pachter and his colleagues, including Verastem researcher Irina Shapiro, PhD, who led the study, found that MPM cells lacking Merlin, the product of the neurofibromatosis type 2 (NF2) tumor suppressor gene, were especially sensitive to FAK inhibition in vivo and in vitro. After 29 days of treatment with VS-4718, mice with Merlin-negative disease had significantly smaller tumors than mice with Merlin-positive disease. Similarly, VS-4718 significantly decreased the proliferation of Merlin-negative MPM cell lines, compared to Merlin-positive MPM cells.

“The identification of the enrichment marker, Merlin, might help to identify mesothelioma patients who may benefit most from FAK inhibitor treatment,” says Pachter.

FAK also helps regulate the self-renewal of cancer stem cells (CSC), which are linked to metastases and recurrence. By killing CSCs, Pachter says, FAK inhibitors have the potential to prolong survival in patients with MPM. That idea was borne out in mouse experiments as part of the new work: Pachter and his team reported that mice with Merlin-negative disease treated first with combination chemotherapy (cisplatin and pemetrexed) and then with VS-4718 had more durable responses than mice treated with chemotherapy alone.

Merlin is lacking in 40% to 50% of patients with MPM, suggesting that many may benefit from a FAK inhibitor like VS-4718. Targeting FAK may work with multiple types of cancer, too. For example, another Verastem drug, defactinib (VS-6063), is under study in patients with MPM as well as ovarian and non–small cell lung cancers.