TY - JOUR
T1 - Acquired resistance to the TRK inhibitor entrectinib in colorectal cancer
AU - Russo, Mariangela
AU - Misale, Sandra
AU - Wei, Ge
AU - Siravegna, Giulia
AU - Crisafulli, Giovanni
AU - Lazzari, Luca
AU - Corti, Giorgio
AU - Rospo, Giuseppe
AU - Novara, Luca
AU - Mussolin, Benedetta
AU - Bartolini, Alice
AU - Cam, Nicholas
AU - Patel, Roopal
AU - Yan, Shunqi
AU - Shoemaker, Robert
AU - Wild, Robert
AU - di Nicolantonio, Federica
AU - Sartore-Bianchi, Andrea
AU - Li, Gang
AU - Siena, Salvatore
AU - Bardelli, Alberto
N1 - M.Russo non risulta affiliata correttamente in questa pubblicazione
PY - 2016/1/1
Y1 - 2016/1/1
N2 - 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.
AB - 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.
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U2 - 10.1158/2159-8290.CD-15-0940
DO - 10.1158/2159-8290.CD-15-0940
M3 - Article
AN - SCOPUS:84954060726
VL - 6
SP - 36
EP - 44
JO - Cancer Discovery
JF - Cancer Discovery
SN - 2159-8274
IS - 1
ER -