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Rat sarcoma (RAS) oncogenes have intensively been investigated during the last decades. Taking into account all human tumours, Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) gene is the most frequently mutated (about 22%) among the three isoforms, followed by Neuroblastoma RAS Viral Oncogene Homolog (NRAS) (8%) and Harvey Rat Sarcoma Viral Oncogene Homolog (HRAS) (3%). In the last years, careful attention has been paid on KRAS and NRAS gene mutations in non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC) patients because of their prognostic and predictive roles. In particular, a large body of literature data has been generated investigating clinical outcomes of targeted treatments in NSCLC and CRC KRAS- and NRAS-mutated patients. The latest evidences are here reviewed, providing also an overview of the real-world RAS mutation testing practice across different Italian laboratories. On this basis, we propose a knowledge-based system, www.rasatlas.com, to support the healthcare personnel in the management of patients featuring RAS gene mutations in the landscape of precision oncology., Competing Interests: Conflict of interest statement Umberto Malapelle has received personal fees (as consultant and/or speaker bureau) from Boehringer Ingelheim, Roche, MSD, Amgen, ThermoFisher Scientifics, Diaceutics, GSK, Merck and AstraZeneca, unrelated to the current work. Francesco Passiglia has received personal fees (as consultant and/or speaker bureau) from MSD, AstraZeneca, Boehringer Ingelheim, BMS and Pfizer, unrelated to the current work. Alfonso De Stefano received personal fees (as consultant and/or speaker) from Amgen, Merck and Italfarmaco, unrelated to the current work. Fabio Pagni has received personal fees (as consultant and/or speaker bureau) from, MSD, GSK, Merck and AstraZeneca, unrelated to the current work. Filippo Pietrantionio has received honoraria from Amgen, Roche, Merck-Serono, Bayer, Servier, Lilly and Sanofi, and research grants from BMS, unrelated to the current work. Sara Pilotto has received personal fees (as consultant and/or speaker bureau) from Boehringer Ingelheim, BMS, Roche, MSD and AstraZeneca, unrelated to the current work. Luisella Righi has received personal fees (as consultant and/or speaker bureau) from Astra Zeneca, Novartis, Amgen and Boehringer Ingelheim, unrelated to the current work. Marcello Tiseo received speakers' and consultants’ fee from Astra-Zeneca, Pfizer, Eli-Lilly, BMS, Novartis, Roche, MSD, Boehringer Ingelheim, Otsuka, Takeda and Pierre Fabre, and institutional research grants from Astra-Zeneca, Boehringer Ingelheim, unrelated to the current work. Giancarlo Troncone reports personal fees (as speaker bureau or advisor) from Roche, MSD, Pfizer and Bayer, unrelated to the current work. Silvia Novello reports personal fees (as speaker bureau or advisor) from Eli Lilly, MSD, Roche, BMS, Takeda, Pfizer, Astra Zeneca and Boehringer Ingelheim, unrelated to the current work. The other authors declare no potential conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Unlabelled: 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., (©2015 American Association for Cancer Research.)