An environment of resistance

A team led by Ludwig Harvard’s Sandro Santagata and George Demetri reported in a February paper in JCO Precision Oncology their analyses of the mechanism(s) of resistance to TRK-fusion inhibitors (TRKi) in a patient diagnosed with a metastatic sarcoma that originated in the pelvis. Analysis of the sarcoma revealed that the cancer harbored a chimeric genomic fusion of the NTRK1 gene. After an initial major response to larotrectinib, a first-generation TRKi, disease progression occurred with subsequent response when treated with a second-generation TRKi, selitrectinib. Using a multiplex spatial imaging system developed at Ludwig Harvard, and next-generation DNA sequencing methods, Sandro, George and their colleagues analyzed the evolution of drug resistance in the patient’s tumors. They identified a gain-of-function mutation in the KRAS gene that led to reactivation of the targeted signal transduction pathway and consequent tumor progression. The researchers also described how the activation of KRAS-induced changes in the infiltrating immune cell profile of the tumor microenvironment, including a significant increase in intratumoral cytotoxic T cells and macrophages. Their findings help define mechanisms of resistance to TRKis and suggest novel strategies to treat resistant disease. These could include a combination of immunotherapy and novel TRKis.

This article appeared in the August 2020 issue of Ludwig Link. Click here to download a PDF (2 MB).


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