2658-6533Research Results in Biomedicine2658-653310.18413/2658-6533-2025-11-1-0-13680Genetics<strong>Pathway directed mechanisms of anti-EGFR resistance in colorectal cancer (review)</strong><strong>Pathway directed mechanisms of anti-EGFR resistance in colorectal cancer (review)</strong>LebedevaAlexandra A.LebedevaAlexandra A.lebedeva_a_a_1@staff.sechenov.ruKavunAlexandra I.KavunAlexandra I.kavun@oncoatlas.ruBelovaEkaterina V.BelovaEkaterina V.belova@oncoatlas.ruAntonovaTatiana G.AntonovaTatiana G.tattg@mail.ruSemenovaAnna B.SemenovaAnna B.gkob1@zdrav.mos.ruKuznetsovaOlesya A.KuznetsovaOlesya A.lessya.kuznetsova@gmail.comGrigorevaTatiana V.GrigorevaTatiana V.grigoreva@oncoatlas.ruVeselovskyEgor M.VeselovskyEgor M.egor.veselovsky@gmail.comTaraskinaAnastasiia N.TaraskinaAnastasiia N.taraskina@oncoatlas.ruIvanovMaxim V.IvanovMaxim V.maxim.ivanov@oncoatlas.ruMileykoVladislav A.MileykoVladislav A.mileyko@oncoatlas.ruTryakinAlexey A.TryakinAlexey A.atryakin@mail.ruFedyaninMikhail Y.FedyaninMikhail Y.fedyaninmu.ronc@gmail.comPokataevIlya A.PokataevIlya A.pokia@mail.ruByakhovaMariya M.ByakhovaMariya M.biakhovamm@gmail.comGalkin,Vsevolod N.Galkin,Vsevolod N.galkin_v_n_1@staff.sechenov.ru202511100

Background: Targeting the epidermal growth factor receptor (EGFR) with cetuximab or panitumumab (anti-EGFR MAb) has been historically reserved for patients with RAS/BRAF wild-type advanced colorectal cancer (CRC). However, results of recent studies including PARADIGM and PRESSING evaluating the role of negative hyperselection of RAS wild-type CRC by alterations in other genes suggest that other genomic factors beyond RAS/BRAF/ERBB2 might influence the response to anti-EGFR MAbs in CRC. Although vast, current data on the predictive role of individual biomarkers to anti-EGFR MAb is often misunderstood. The aim of the study: In this review, in light of recent findings, we aimed to summarize existing data on the influence of various signaling pathways and their individual components along with nongenomic factors for the optimal patient selection for anti-EGFR MAbs. Materials and methods: To collect available information on possible mechanisms of resistance to anti-EGFR MAb in patients with colorectal cancer we searched PubMed and ClinicalTrials.gov in May 2024. We also searched proceedings from the major oncology conferences ESMO, ASCO, and ASCO GI up to May 2024. We further scanned reference lists from eligible publications. Results: In this review we outline current knowledge on the mechanisms of resistance to anti-EGFR MAbs beyond traditional KRAS/NRAS/BRAF mutations in CRC. We focus on the alterations of genes involved in signaling pathways downstream of EGFR that can be detected by comprehensive tumor profiling in real-world clinical practice. Conclusion: Despite many mechanisms affecting various signaling pathways beyond the traditional KRAS/NRAS/BRAF mutations that are thought to be implicated in the resistance to anti-EGFR MAb in CRC, future efforts are needed to clarify their significance. Ongoing sequencing efforts will clarify the need for expanding the list of alterations routinely tested for the selection of candidates for anti-EGFR MAb

Background: Targeting the epidermal growth factor receptor (EGFR) with cetuximab or panitumumab (anti-EGFR MAb) has been historically reserved for patients with RAS/BRAF wild-type advanced colorectal cancer (CRC). However, results of recent studies including PARADIGM and PRESSING evaluating the role of negative hyperselection of RAS wild-type CRC by alterations in other genes suggest that other genomic factors beyond RAS/BRAF/ERBB2 might influence the response to anti-EGFR MAbs in CRC. Although vast, current data on the predictive role of individual biomarkers to anti-EGFR MAb is often misunderstood. The aim of the study: In this review, in light of recent findings, we aimed to summarize existing data on the influence of various signaling pathways and their individual components along with nongenomic factors for the optimal patient selection for anti-EGFR MAbs. Materials and methods: To collect available information on possible mechanisms of resistance to anti-EGFR MAb in patients with colorectal cancer we searched PubMed and ClinicalTrials.gov in May 2024. We also searched proceedings from the major oncology conferences ESMO, ASCO, and ASCO GI up to May 2024. We further scanned reference lists from eligible publications. Results: In this review we outline current knowledge on the mechanisms of resistance to anti-EGFR MAbs beyond traditional KRAS/NRAS/BRAF mutations in CRC. We focus on the alterations of genes involved in signaling pathways downstream of EGFR that can be detected by comprehensive tumor profiling in real-world clinical practice. Conclusion: Despite many mechanisms affecting various signaling pathways beyond the traditional KRAS/NRAS/BRAF mutations that are thought to be implicated in the resistance to anti-EGFR MAb in CRC, future efforts are needed to clarify their significance. Ongoing sequencing efforts will clarify the need for expanding the list of alterations routinely tested for the selection of candidates for anti-EGFR MAb

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