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The RAS oncogene is among the most commonly mutated in cancer. RAS mutations are identified in about half of patients diagnosed with metastatic colorectal cancer (mCRC), conferring poor prognosis and lack of response to anti-epidermal growth factor receptor (EGFR) antibodies. In the last decades, several investigational attempts failed in directly targeting RAS mutations, thus RAS was historically regarded as 'undruggable'. Recently, novel specific KRAS G12C inhibitors showed promising results in different solid tumors, including mCRC, renewing interest in this biomarker as a target. In this review, we discuss different strategies of RAS targeting in mCRC, according to literature data in both clinical and preclinical settings. We recognized five main strategies focusing on those more promising: direct RAS targeting, targeting the mitogen-activated protein kinase (MAPK) pathway, harnessing RAS through immunotherapy combinations, RAS targeting through metabolic pathways, and finally other miscellaneous approaches. Direct KRAS G12C inhibition is emerging as the most promising strategy in mCRC as well as in other solid malignancies. However, despite good disease control rates, tumor response and duration of response are still limited in mCRC. At this regard, combinational approaches with anti-epidermal growth factor receptor drugs or checkpoint inhibitors have been proposed to enhance treatment efficacy, based on encouraging results achieved in preclinical studies. Besides, concomitant therapies increasing metabolic stress are currently under evaluation and expected to also provide remarkable results in RAS codon mutations apart from KRAS G12C . In conclusion, based on hereby reported efforts of translational research, RAS mutations should no longer be regarded as 'undruggable' and future avenues are now opening for translation in the clinic in mCRC., Competing Interests: Disclosure SS is an advisory board member for Amgen, Bayer, Bristol-Myers Squibb, CheckmAb, Clovis, Daiichi-Sankyo, Merck, Roche-Genentech, and Seattle Genetics. ASB is an advisory board member for Amgen, Bayer, Sanofi, and Servier. FS reports grants from Pfizer, lecture fees from Novartis and Merck Sharp & Dohme, and has served on advisory board for GlaxoSmithKline, outside the submitted work. The other authors declare no conflicts of interest., (Copyright © 2021. Published by Elsevier Ltd.)

With the development of trastuzumab for metastatic breast cancer a new era began in cancer drug development. The drug-diagnostic codevelopment model with its clinical enrichment trial design has enabled development of target specific drugs for molecular defined subsets of patients. Since the simultaneous approval of trastuzumab and the HercepTest in 1998, the number of FDA-approved drug-companion diagnostic combinations within oncology and hematology have steadily increased. By June 2021, the number of drugs that have a companion diagnostic (CDx) linked to its use has reached 46. For these drugs, the CDx assays play an important role in defining the patient population likely to respond and without the assay they will often lose their value. This short article is based on an analysis of the FDA List of Cleared or Approved Companion Diagnostic Devices and relevant information in the Drugs@FDA, and will focus on the drug-CDx combinations, drug classes, clinical development, and the regulatory path and status., (Copyright © 2021 The Author. Published by Elsevier Ltd.. All rights reserved.)