Investigators at the Massachusetts General Hospital (MGH) Cancer Center have identified the first genetic mechanisms conferring acquired resistance to a promising group of targeted cancer drugs. In a paper appearing in the March issue of Cancer Discovery, the researchers describe finding novel resistance mechanisms in three patients receiving fibroblast growth factor receptor (FGFR) inhibitor treatment for a type of liver cancer. While many patients show impressive responses to this treatment, the appearance of new drug-resistant mutations in the FGFR gene as tumors progress– and even several different mutations within samples from individual patients – suggests the need for drugs that block multiple pathways to avoid the resumption of tumor progression.
“FGFR represents an important therapeutic target in many cancers,” says lead author Lipika Goyal, MD, MPhil, of the MGH Cancer Center. “Our findings may inform future strategies for detecting resistance mechanisms and inducing more durable responses in FGFR2 fusion-positive intrahepatic cholangiocarcinoma and possibly other cancers in which the FGFR pathway is being explored as a therapeutic target.”
Cancers driven by mutations that activate FGFR include certain tumors of the lung, breast, stomach and bladder. From 10 to 20 percent of cases of intrahepatic cholangiocarcinoma (ICC) – the second most common tumor originating in the liver – are thought to be driven by FGFR2 fusion mutations. An FGFR inhibitor called BGJ398 is currently in a phase 2 clinical trial for treatment of advanced ICC patients whose FGFR-driven cancers progressed after chemotherapy, and while preliminary data from the trial reported a significant response to treatment, as with most targeted therapies, resistance inevitably develops.
The MGH team analyzed samples from three patients with FGFR2 fusion-positive ICC enrolled in the BGJ398 trial for whom treatment led to a 30 to 50 percent tumor reduction, followed by disease progression after four to eight months. Analysis of cell-free DNA (cfDNA) from blood samples taken before BGJ398 treatment and after tumor progression revealed that one to five new FGFR2 kinase domain mutations had developed in each patient. A common mutation that emerged in all three patients was FGFR2 V564F, a gatekeeper mutation which interferes with the binding of BGJ398 to the FGFR. The other mutations altered the conformation of FGFR2, leading to continuous signaling through the pathway.
Rapid autopsy samples from one patient who died after having disease progression on BGJ398 treatment revealed that different metastases harbored distinct FGFR2 mutations, thus demonstrating that multiple different mechanisms can confer resistance in individual patients. Treating BGJ398-resistant cell lines with several other FGFR inhibitors showed that other structurally distinct drugs in the same class may be able to overcome FGFR2 resistance mutations.
“As seen with the development of resistance to other targeted treatment drugs, the mechanisms we identified are heterogeneous, and different therapeutic approaches may be necessary to overcome those resistance mechanisms,” says senior and co-corresponding author Andrew X. Zhu, MD, PhD, director of Liver Cancer Research at the MGH Cancer Center. “In addition to helping us understand why patients developed tumor progression within months of beginning a rationally chosen targeted therapy, our findings also suggest that tumor biopsies may underestimate resistance mechanisms. Repeat analysis of cfDNA may provide a more comprehensive picture of the mechanisms at play.”
Goyal is an instructor and Zhu is a professor of Medicine at Harvard Medical School. Additional co-authors of the Cancer Discovery paper include Ryan Corcoran, MD, PhD, Supriya Saha, MD, PhD, Leah Liu, PhD, Dejan Juric, MD, and Nabeel Bardeesy, PhD, of the MGH Cancer Center. Funding for this research was provided by the Cholangiocarcinoma Foundation, TargetCancer Foundation, the MGH Executive Committee on Research Fund for Medical Discovery Award, the National Institutes of Health/National Cancer Institute Gastrointestinal Cancer SPORE, The V Foundation for Cancer Research, and the Jonathan Kraft Translational Award, among others.
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $800 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2016 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America’s Best Hospitals."
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