growth factor receptor (FGFR) inhibitors are a new family of targeted agents designed to
inhibit the action of the fibroblast growth factor receptor, which is
often overexpressed in lung, bladder, biliary and breast cancers.
A new study by researchers at The Ohio State University Comprehensive
Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute (OSUCCC - James) has identified a mechanism by which
cancer cells develop resistance to the FGFR inhibitors.
‘A mechanism by which cancer cells develop resistance to the fibroblast growth factor receptor (FGFR) inhibitors has been identified by researchers.’
Published in the journal Molecular Cancer Therapeutics
study also found that use of a second inhibitor might improve the
effectiveness of these drugs by possibly preventing resistance, and it
recommends that clinical trials should be designed to include a second
"Understanding how drug resistance develops can help in the design
of new agents or strategies to overcome resistance," says principal
investigator Sameek Roychowdhury, assistant professor of
medicine and of pharmacology in the Division of Medical Oncology at the
OSUCCC - James.
"Our paper demonstrates in a laboratory model how cancer can evade
this class of therapy, and it provides insights into how clinical trials
for these therapies could be further developed to overcome the problem
of drug resistance," he adds.
The laboratory study by Roychowdhury and his colleagues induced
resistance to the FGFR inhibitor BGJ398 in lung- and bladder-cancer
cells after long-term exposure to the agent. The researchers then found
that, while the drug continued to inhibit FGFR activity in the resistant
cells, its inhibition of FGFR signaling had no appreciable effect on
the cells' survival.
Examining other molecules in the FGFR pathway, the researchers found
that a regulatory protein called Akt remained highly active, even
during FGFR inhibition. Akt, a key regulator of cell biology, is
directly involved in cell proliferation, cell survival and cell growth.
Furthermore, they found that by inhibiting Akt they could
significantly slow cell proliferation, cell migration and cell invasion
in the lung cancer and bladder cancer cells.
"Fibroblast growth factor receptor inhibitors are new therapies
being developed in clinical trials for patients whose cancer cells have
genetic alterations in this family of genes," says Roychowdhury, a
member of the OSUCCC - James Translational Therapeutics Program. "We
believe our findings will help improve this therapy for lung, bladder
and other cancers."