Off-Target Alterations Drive Resistance to TRK Inhibitors in Some Cancers

Fusions affecting genes for tropomyosin receptor kinases (TRK) occur in many cancers. These can be treated with TRK inhibitors, such as larotrectinib, entrectinib, LOXO-195, and repotrectinib. Mutations in the TRK kinase domain that reduce or prevent drug binding sometimes confer resistance, but do not explain all cases. Cocco, Schram, and colleagues analyzed tumor biopsies and circulating cell-free DNA (cfDNA) from patients with TRK gene fusions. Patient 1′s pancreatic cancer, which had become resistant to larotrectinib, acquired a BRAF^V600E mutation; the matched patient-derived xenografts in mice treated with larotrectinib had outgrowth of a BRAF^V600E subclone at resistance. Disease progression on the second-generation TRK inhibitor LOXO-195 (which is intended to bypass resistance caused by mutations in the TRK kinase domain) was rapid, and expression of BRAF^V600E in a pancreatic cancer cell line harboring an NTRK1 fusion resulted in LOXO-195 resistance. Early tumor regression was observed upon combination treatment of this patient with a RAF and a MEK inhibitor (dabrafenib and trametinib, respectively); however, a preexisting, previously subclonal KRAS^G12D mutation was detected in cfDNA, and radiographic progression followed. Patient 2′s colorectal cancer, which had become resistant to LOXO-195, exhibited hotspot KRAS mutations; a response was observed upon subsequent treatment with LOXO-195, but metastasis to the liver characterized by a KRAS^G12A mutation was later noted. Further, expression of KRAS^G12A or KRAS^G12D in colorectal cancer cell lines with TRK fusions caused resistance to larotrectinib and LOXO-195. Patient 3′s cholangiocarcinoma, which had become resistant to the first-generation TRK inhibitor entrectinib, exhibited high-level focal MET amplification along with MET protein overexpression, and disease progression upon treatment with LOXO-195 was rapid. Treatment with the multikinase MET inhibitor crizotinib and LOXO-195 initially caused tumor shrinkage and disappearance of the NTRK fusion and MET amplification in cfDNA; MET amplification and missense mutations were noted after progression. These findings provide evidence that some TRK fusion–positive cancers can become resistant to both first- and second-generation TRK inhibitors by acquiring genomic alterations that result in the activation of the MAPK pathway; additionally, they suggest that combination treatment with TRK and MEK inhibitors may help manage this resistance.

Cocco E, Schram AM, Kulick A, Misale S, Won HH, Yaeger R, et al. Resistance to TRK inhibition mediated by convergent MAPK pathway activation. Nat Med 2019 Aug 12 [Epub ahead of print].

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