TERAPIAS-ALVO EM ALTERAÇÕES MOLECULARES EMERGENTES (KRAS G12C, BRAF E HER2) NO CÂNCER DE CÓLON: BASES BIOLÓGICAS, EVIDÊNCIAS CLÍNICAS E IMPACTO NA MEDICINA DE PRECISÃO
DOI:
https://doi.org/10.63330/aurumpub.036-020Palavras-chave:
BRAF V600E, Câncer de cólon, HER2, KRAS G12C, Medicina de precisãoResumo
O câncer de cólon apresenta elevada heterogeneidade molecular, sendo as alterações em KRAS G12C, BRAF V600E e HER2 determinantes na estratificação terapêutica e na consolidação da medicina de precisão. Este estudo teve como objetivo analisar as bases biológicas dessas alterações, as evidências clínicas relacionadas às terapias-alvo correspondentes e seu impacto na prática oncológica contemporânea. Trata-se de revisão bibliográfica qualitativa, realizada em bases de dados internacionais, com seleção de estudos publicados entre 2021 e 2026. Os resultados evidenciam que a mutação KRAS G12C, anteriormente considerada “indrogável”, tornou-se alvo terapêutico viável com o desenvolvimento de inibidores seletivos, especialmente eficazes quando combinados a anticorpos anti-EGFR, a fim de reduzir mecanismos de reativação compensatória. No subtipo BRAF V600E, estratégias combinatórias envolvendo inibidores de BRAF, MEK e bloqueio de EGFR demonstraram melhora significativa de sobrevida, redefinindo o padrão terapêutico para esse grupo de pior prognóstico. Já a amplificação ou superexpressão de HER2 configura subgrupo distinto, frequentemente resistente a terapias anti-EGFR isoladas, mas responsivo ao duplo bloqueio anti-HER2. Apesar dos avanços, a resistência primária e adquirida, associada à heterogeneidade tumoral e à plasticidade metabólica, permanece como desafio clínico relevante. Conclui-se que a integração entre biologia molecular, monitoramento genômico e estratégias combinatórias é essencial para otimizar desfechos e consolidar a medicina personalizada no câncer de cólon.
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DI NICOLANTONIO, Federica; VITIELLO, Paolo; MARSONI, Stefano; SIENA, Salvatore; TABERNERO, Josep; TRUSOLINO, Livio; BERNARDS, René; BARDELLI, Alberto. Precision oncology in metastatic colorectal cancer — from biology to medicine. Nature Reviews Clinical Oncology, v. 18, p. 506-525, 2021.
HARROLD, Emily; KEANE, Fiona; WALCH, Hannah; CHOU, Jennifer; SINOPOLI, Joseph; PALLADINO, Stephanie; AL-RAWI, Dana; CHADALAVADA, Karthik; MANCA, Paola; CHALASANI, Sushma; YANG, Jiajia; CERCEK, Andrea; SHIA, Jinru; CAPANU, Marinela; BAKHOUM, Samuel; SCHULTZ, Nikolaus; CHATILA, Walid; YAEGER, Rona. Molecular and clinical determinants of acquired resistance and treatment duration for targeted therapies in colorectal cancer. Clinical Cancer Research, v. 30, p. 2672-2683, 2024.
HOFMANN, Matthias; GERLACH, Daniel; MISALE, Simone; PETRONCZKI, Mark; KRAUT, Norbert. Expanding the reach of precision oncology by drugging all KRAS mutants. Cancer Discovery, v. 12, p. 924-937, 2022.
HUANG, Li; GUO, Zhen; WANG, Feng; FU, Lei. KRAS mutation: from undruggable to druggable in cancer. Signal Transduction and Targeted Therapy, v. 6, 2021.
HWANG, Seung; SEO, Young; PARK, Seung; KIM, Seong; MOON, In; LIU, Yan; KIM, Sung; PAK, Eun; JUNG, Sung; KIM, Hyeon; JEON, Kyung; SEO, Seung; SUNG, In; LEE, Hyun; PARK, Seong; NA, Young; KIM, Tae; KWON, Young. Targeting the HER2-ELF3-KRAS axis: a novel therapeutic strategy for KRAS G13D colorectal cancer. Molecular Cancer, v. 24, 2025.
JOHNSON, Daniel; CHEE, Ching; WONG, Wai; LAM, Raymond; TAN, Ivan; BROWN, Benjamin. Current advances in targeted therapy for metastatic colorectal cancer: clinical translation and future directions. Cancer Treatment Reviews, v. 125, p. 102700, 2024.
KIM, Jihoon; KIM, Hyejin; NAM, Minji; CHAE, Young. Tissue-agnostic biomarkers in solid tumors: current approvals and emerging candidates. Cancer Metastasis Reviews, v. 44, 2025.
LI, Fang; LIN, Yu; LI, Rui; SHEN, Xin; XIANG, Meng; XIONG, Guang; ZHANG, Kai; XIA, Tao; GUO, Jian; MIAO, Zhi; LIAO, Yong; ZHANG, Xin; XIE, Lei. Molecular targeted therapy for metastatic colorectal cancer: current and evolving approaches. Frontiers in Pharmacology, v. 14, 2023.
LIU, Zhe; LI, Yu; WANG, Shuo; WANG, Ying; SUI, Meng; LIU, Jie; CHEN, Peng; WANG, Jun; ZHANG, Yan; DANG, Cheng; HOU, Pei. Genome-wide CRISPR screening identifies PHF8 as an effective therapeutic target for KRAS- or BRAF-mutant colorectal cancers. Journal of Experimental and Clinical Cancer Research, v. 44, 2025.
MINA, Sarah; SHANSHAL, Mohammed; LEVENTAKOS, Konstantinos; PARIKH, Kunal. Emerging targeted therapies in non-small-cell lung cancer. Cancers, v. 17, 2025.
MIYASHITA, Hiroki; KATO, Shumei; HONG, David. KRAS G12C inhibitor combination therapies: current evidence and challenge. Frontiers in Oncology, v. 14, 2024.
POTOCKI, Piotr; WÓJCIK, Piotr; CHMURA, Łukasz; GOC, Bartosz; FEDEWICZ, Michał; BIELAŃSKA, Zuzanna; SWADŹBA, Joanna; KONOPKA, Karolina; KWINTA, Łukasz; WYSOCKI, Piotr. Clinical characterization of targetable mutations (BRAF V600E and KRAS G12C) in advanced colorectal cancer — a nation-wide study. International Journal of Molecular Sciences, v. 24, 2023.
ROJAS, María; MANZI, Matteo; MADURGA, Sergi; VELÁSQUEZ, Felipe; ROMERO, Manuel; MARÍN, Silvia; CASCANTE, Marta; MAUREL, Joan. Metabolic plasticity drives specific mechanisms of chemotherapy and targeted therapy resistance in metastatic colorectal cancer. Exploration of Targeted Anti-tumor Therapy, v. 6, 2025.
RUAN, Dan; WU, Hao; XU, Ying; MUNSTER, Pamela; DENG, Yong; RICHARDSON, Grant; YAN, Dong; LEE, Michael; LEE, Kwan; PAN, Hong; HAGER, Scott; LI, Xia; WEI, Shujun; HOU, Xia; UNDERHILL, Christopher; MILLWARD, Michael; NORDMAN, Ingrid; ZHANG, Jie; SHAN, Jie; HAN, Guang; GREWAL, Jaskaran; GADGEEL, Shirish; SANBORN, Rebecca; HUH, Sun; HU, Xia; ZHANG, Ying; XIANG, Zheng; LUO, Lin; XIE, Xin; SHI, Zhen; WANG, Yi; ZHANG, Li; WANG, Feng; XU, Rui. Garsorasib, a KRAS G12C inhibitor, with or without cetuximab, an EGFR antibody, in colorectal cancer cohorts of a phase II trial in advanced solid tumors with KRAS G12C mutation. Signal Transduction and Targeted Therapy, v. 10, 2025.
SHI, Yifan; ZHENG, Hao; WANG, Tao; ZHOU, Shuo; ZHAO, Shuang; LI, Ming; CAO, Bo. Targeting KRAS: from metabolic regulation to cancer treatment. Molecular Cancer, v. 24, 2025.
SHIRAVI, Sara; MOTTAGHI-DASTJERDI, Neda; SHAHBAZI, Bahareh; AHMADI, Niloofar; SOLTANY-REZAEE-RAD, Mohammad; GHORBANI, Amir; MONTAZERI, Hamed. A systems biology approach to identify key targets in KRAS/BRAF-mutated colorectal cancer. Discover Oncology, v. 16, 2025.
SRIVASTAVA, Shalini; ANAND, Ankit; KANDHULA, Akhila; JAISWAL, Pradeep; KUMAR, Sandeep; GULATI, Manish; SACHDEVA, Manish; BEHL, Tapan. Precision medicine in colorectal cancer: targeted therapies and biomarker insights. Current Cancer Drug Targets, 2025.
SULLO, Francesco; GALLIO, Chiara; MATTEUCCI, Laura; BITTONI, Andrea; MURATORE, Marco; ESPOSITO, Luca; CEREDI, Beatrice; GALLO, Giuseppe; ULIVI, Paola; RAPPOSSELLI, Ilaria; PASSARDI, Andrea. Personalized therapy in metastatic colorectal cancer: biomarker-driven use of biologics. Expert Opinion on Biological Therapy, v. 25, p. 947-965, 2025.
TAKEDA, Masayuki; YOSHIDA, Shogo; INOUE, Tatsuya; SEKIDO, Yoshitaka; HATA, Tomohiro; HAMABE, Akihiro; OGINO, Tomoya; MIYOSHI, Norikatsu; UEMURA, Masaki; YAMAMOTO, Hirofumi; DOKI, Yuichiro; EGUCHI, Hidetoshi. The role of KRAS mutations in colorectal cancer: biological insights, clinical implications, and future therapeutic perspectives. Cancers, v. 17, 2025.
VELUSWAMY, Ramaswamy; MACK, Philip; HOULDSWORTH, Jane; ELKHOULY, Eman; HIRSCH, Fred. KRAS G12C-mutant non-small-cell lung cancer: biology, developmental therapeutics, and molecular testing. The Journal of Molecular Diagnostics, 2021.
YANG, En; WALDRUP, Benjamin; VELAZQUEZ-VILLARREAL, Eduardo. Precision oncology through dialogue: AI-HOPE-RTK-RAS integrates clinical and genomic insights into RTK-RAS alterations in colorectal cancer. Biomedicines, v. 13, 2025.
YANG, Yifan; ZHANG, Hui; HUANG, Shuo; CHU, Qiang. KRAS mutations in solid tumors: characteristics, current therapeutic strategy, and potential treatment exploration. Journal of Clinical Medicine, v. 12, 2023.
ZHAO, Yanan; MURCIANO-GOROFF, Yael; XUE, Jiali; ANG, Amanda; LUCAS, Jordan; MAI, Tiffany; DA CRUZ PAULA, Anna; SAIKI, Aya; MOHN, Daniel; ACHANTA, Pavan; SISK, Austin; ARORA, Karan; ROY, Rahul; KIM, Dong; LI, Cheng; LIM, Lee; LI, Ming; BAHR, Andrew; LOOMIS, Brian; DE STANCHINA, Elisa; REIS-FILHO, Jorge; WEIGELT, Britta; BERGER, Michael; RIELY, Gregory; ARBOUR, Kathryn; LIPFORD, Joshua; LI, Bin; LITO, Piro. Diverse alterations associated with resistance to KRAS(G12C) inhibition. Nature, v. 599, p. 679-683, 2021.
ZHU, Chao; GUAN, Xia; ZHANG, Xue; LUAN, Xi; SONG, Zhen; CHENG, Xia; ZHANG, Wei; QIN, Jian. Targeting KRAS mutant cancers: from druggable therapy to drug resistance. Molecular Cancer, v. 21, 2022.
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