Research Reveals Evolution of TRK-fusion Inhibitor Resistance in Cancer

The evolutionary process cancer cells use to resist the drug LOXO-101 was described in a presentation at the American Association for Cancer Research 2016 Annual Meeting.1

"We're showing outstanding results with kinase inhibitors, including LOXO-101, to target specific activating genetic abnormalities. However, cancers often evolve in response to these drugs, acquiring or utilizing additional genetic changes that confer resistance.

“This study shows mechanisms that cancers caused by fusion of the TRK gene use to evade targeted therapies. We hope that by designing drugs to target these mechanisms of resistance, we can augment and prolong the duration of response experienced by patients using LOXO-101 and other medicines in the family of tyrosine kinase inhibitors," explained Robert C. Doebele, MD, PhD, member of University of Colorado Cancer Center, who presented the data and have participated in clinical investigations of LOXO-101.

LOXO-101, a kinase inhibitor of TRK-fusion genes, which drive a subset of cancers, is currently being evaluated in promising phase 1 and phase 2 clinical trials. This study exposed a library of cells with activating TRK fusions to varied concentrations of LOXO-101 and then investigated the cells that survived. The researchers identified changes in the TRK fusion genes that made the cells resistant to LOXO-101.

"Our goal is to stay a step ahead, to predict and eliminate the pathways that cancer uses to evolve around these drugs," Doebele said.

The resistance mechanisms identified in this study mirror results from related studies exploring resistance mechanisms of other kinase-driven cancers treated with kinase inhibitors (notably, ALK-positive lung cancers treated with crizotinib). So, the findings may have implications beyond just resistance to treatments targeting the TRK-fusion.

"This assists our current clinical trial. Tumors that develop resistance to LOXO-101 could be screened for these changes, allowing the development and use of interventions [that] stop these escape pathways," Doebele said.

"But more generally, this study is further validation of resistance pathways that may be shared by many kinase-driven cancers. Treating these pathways upon tumor progression or even before tumor progression could help patients with many cancers see longer-lasting benefit from many kinds of tyrosine kinase inhibitors."


1. Estrada-Bernal A, Le AT, Tuch B, et al. Identification of TRKA and TRKB kinase domain mutations that induce resistance to a pan-TRK inhibitor. Presentation at: American Association for Cancer Research 2016 Annual Meeting; April 16-20, 2016; New Orleans, LA. Abstract LB-118.

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