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Early attempts to apply single\u2010agent\n                    <jats:italic>BRAF<\/jats:italic>\n                    <jats:sup>V600<\/jats:sup>\n                    inhibition failed because of rapid acquired resistance and reactivation of mitogen\u2010activated protein kinase signaling. Over the last decade, rational combinations (BRAF inhibitors and epidermal growth factor receptor inhibitors with or without mitogen\u2010activated protein kinase kinase inhibitors) have become the standard of care in the refractory setting and are now being evaluated upfront, whereas a wave of next\u2010generation approaches (extracellular signal\u2010regulated kinase and SHP2 inhibitors, receptor tyrosine kinase\u2010targeted agents, and immunotherapy combinations) aims to prevent or overcome resistance. The objective of this comprehensive review was to summarize historic therapeutic approaches, current standards, and the mechanistic rationale and clinical development of next\u2010generation strategies to combat resistance in\n                    <jats:italic>BRAF<\/jats:italic>\n                    <jats:sup>V600<\/jats:sup>\n                    \u2010mutant metastatic colorectal cancer.\n                  <\/jats:p>","DOI":"10.1002\/cncr.70569","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T06:04:56Z","timestamp":1786601096000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The past, present, and future treatment of\n                    <i>BRAF<\/i>\n                    <sup>V600<\/sup>\n                    \u2010mutant metastatic colorectal cancer: A comprehensive 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