Acquired resistance to the TRK inhibitor entrectinib in colorectal cancer

Mariangela Russo, Sandra Misale, Ge Wei, Giulia Siravegna, Giovanni Crisafulli, Luca Lazzari, Giorgio Corti, Giuseppe Rospo, Luca Novara, Benedetta Mussolin, Alice Bartolini, Nicholas Cam, Roopal Patel, Shunqi Yan, Robert Shoemaker, Robert Wild, Federica di Nicolantonio, Andrea Sartore-Bianchi, Gang Li, Salvatore SienaAlberto Bardelli

Research output: Contribution to journalArticlepeer-review

Abstract

Entrectinib is a first-in-class pan-TRK kinase inhibitor currently undergoing clinical testing in colorectal cancer and other tumor types. A patient with metastatic colorectal cancer harboring an LMNA–NTRK1 rearrangement displayed a remarkable response to treatment with entrectinib, which was followed by the emergence of resistance. To characterize the molecular bases of the patient's relapse, circulating tumor DNA (ctDNA) was collected longitudinally during treatment, and a tissue biopsy, obtained before entrectinib treatment, was transplanted in mice (xenopatient), which then received the same entrectinib regimen until resistance developed. Genetic profiling of ctDNA and xenopatient samples showed acquisition of two point mutations in the catalytic domain of NTRK1, p.G595R and p.G667C. Biochemical and pharmacologic analysis in multiple preclinical models confirmed that either mutation renders the TRKA kinase insensitive to entrectinib. These findings can be immediately exploited to design next-generation TRKA inhibitors. Significance: We provide proof of principle that analyses of xenopatients (avatar) and liquid biopsies allow the identification of drug resistance mechanisms in parallel with clinical treatment of an individual patient. We describe for the first time that p.G595R and p.G667C TRKA mutations drive acquired resistance to entrectinib in colorectal cancers carrying NTRK1 rearrangements.

Original languageEnglish
Pages (from-to)36-44
Number of pages9
JournalCancer Discovery
Volume6
Issue number1
DOIs
Publication statusPublished - Jan 1 2016

ASJC Scopus subject areas

  • Oncology

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