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. Cancer Discov; 6(1); 36–44. ©2015 AACR. See related commentary by Okimoto and Bivona, p. 14. This article is highlighted in the In This Issue feature, p. 1

Erratum: Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients

The mismatch repair (MMR) system which detects and corrects base mismatches and insertions and deletions that occur during DNA synthesis is deregulated in approximately 20% of human cancers. MMR-deficient tumors have peculiar properties, including early-onset metastatic potential but generally favorable prognosis, and remarkable response to immune therapy. The functional basis of these atypical clinical features has recently started to be elucidated. Here, we discuss how the biological and clinical features of MMR-deficient tumors might be traced back to their ability to continuously produce new somatic mutations, leading to increased levels of neoantigens, which in turn stimulate immune surveillance. Significance: Tumors carrying defects in DNA MMR accumulate high levels of mutations, a feature linked to rapid tumor progression and acquisition of drug resistance but also favorable prognosis and response to immune-checkpoint blockade. We discuss how the genomic landscape of MMR-deficient tumors affects their biological and clinical behaviors. Cancer Discov; 8(12); 1–11.©2018 AACR.