Understanding the predictive role of K-ras for epidermal growth factor receptor-targeted therapies in colorectal cancer.
The prognosis of metastatic colorectal cancer (mCRC) remains poor regardless of the advances obtained in recent years with new therapeutic agents, surgical procedures, and diagnostic methods. New treatments directed to molecular targets have emerged and are being developed to improve these results, but there is a need to optimize and define the best use of these new approaches. Current use of irinotecan, oxaliplatin, and bevacizumab combined with the long-time standards 5-fluorouracil and leucovorin as first- or second-line treatment for patients with mCRC has resulted in median overall survival figures of > 20 months. Additional improvements in treatment are likely to be facilitated by the use of rationally selected therapeutic agents that target functionally important proteins in tumor cells, such as the epidermal growth factor receptor (EGFR). The activation of EGFR leads to the activation of intracellular effectors involved in intracellular signaling pathways such as the G protein K-Ras. The K-Ras oncoprotein controls transduction of signals required for proliferation, differentiation, and survival, mainly acting as guanosine diphosphate/guanosine triphosphate-regulated binary switches located at the inner surface of the plasma membrane. Monoclonal antibodies (MoAbs) designed to bind to the ectodomain of the EGFR have shown activity in chemorefractory mCRC and in the first-line setting. Cetuximab and panitumumab are MoAbs that bind to the EGFR and thereby inhibit cell proliferation, metastasis, and angiogenesis. Recent clinical data confirm that the efficacy of cetuximab and panitumumab is confined to patients bearing tumors with wild-type K-ras. K-ras mutation analysis may now be considered a new standard of care in the selection of patients for EGFR-targeted therapy.
Ramos
Francisco Javier
FJ
Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain.
Macarulla
Teresa
T
Capdevila
Jaume
J
Elez
Elena
E
Tabernero
Josep
J
D015415:Biomarkers; D002986:Clinical Trials as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D011905:Genes, ras; D006801:Humans; D011379:Prognosis; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D015398:Signal Transduction
D015415:Biomarkers; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras)