FGFR Inhibitors May Offer New Way to Treat Malignant Pleural Mesothelioma

Drugs that inhibit a particular cell signaling pathway might offer a new way to help treat the intractable asbestos cancer, malignant mesothelioma.

Fibroblast growth factor receptor (FGFR) is a tyrosine kinase signaling pathway that plays a fundamental role in the development of embryos, tissue regeneration, and the growth of new blood vessels (angiogenesis).

Recent evidence suggests that it may also impact the development of cancers such as pleural and peritoneal mesothelioma.

Now, research conducted in London and The Netherlands further suggests that a subset of mesothelioma patients may be especially sensitive to drugs that interrupt the FGFR pathway.

Testing FGFR Sensitivity

A research team of scientists at Netherlands Cancer Institute and University College London used a range of tests, including a chemical inhibitor screen and whole exome gene sequencing, to test a panel of 889 cancer cell lines for genetic alterations.

Their tests of both immortalized (altered so that they can replicate indefinitely) and primary mesothelioma cells showed a link between higher sensitivity to FGFR inhibition and a genetic mutation known as BAP1 loss.

“None of the lines harboured genomic alterations of FGFR family members, but rather BAP1 protein loss was associated with enhanced sensitivity to FGFR inhibition,” writes author, Josine Quispel-Janssen, MD, a thoracic oncologist at Netherlands Cancer Institute.

The researchers then confirmed the apparent link between a genetic alteration on the BAP1 gene (BAP1 loss) and FGFR sensitivity in live mice with mesothelioma and in cell samples from human pleural mesothelioma patients.

FGFR and Mesothelioma Survival

Malignant mesothelioma is extremely difficult to diagnose and is even harder to treat. The new study, which was published in the journal Clinical Cancer Research, may give clinicians some additional direction when treating mesothelioma patients who test positive for BAP1 protein loss.

“These data identify a clinically relevant malignant pleural mesothelioma subgroup for consideration of FGFR therapeutics in future clinical studies,” concludes Dr. Quispel-Janssen.

A signaling pathway is a series of chemical reactions that direct the activities of both healthy cells and cancer cells. Other tyrosine kinase signaling pathways, such as EGFR in non-small cell lung cancer, have been targeted successfully with cancer drugs like afatinib.

There are a number of FGFR inhibitors being studied, although their effectiveness varies across cancer types.

Sources:

Quispel-Janssen, JM, et al, “Comprehensive pharmacogenomic profiling of malignant pleural mesothelioma identifies a subgroup sensitive to FGFR inhibition”, October 23, 2017, Clinical Cancer Research, Epub ahead of print, http://clincancerres.aacrjournals.org/content/early/2017/10/21/1078-0432.CCR-17-1172

Chae, YK, et al, “Inhibition of the fibroblast growth factor receptor (FGFR) pathway: the current landscape and barriers to clinical application”, February 2017, Oncotarget, pp. 16052-16074, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5362545/