Mechanisms of resistance to anti-epidermal growth factor receptor inhibitors in metastatic colorectal cancer

Abstract

The prognosis of patients with metastatic colorectal cancer (mCRC) remain poor despite the impressive improvement of treatments observed over the last 20 years that led to an increase in median overall survival from 6 mo, with the only best supportive care, to approximately 30 mo with the introduction of active chemotherapy drugs and targeted agents. The monoclonal antibodies (moAbs) cetuximab and panitumumab, directed against the epidermal growth factor receptor (EGFR), undoubtedly represent a major step forward in the treatment of mCRC, given the relevant efficacy in terms of progression-free survival, overall survival, response rate, and quality of life observed in several phase III clinical trials among different lines of treatment. However, the anti-EGFR moAbs were shown only to be effective in a subset of patients. For instance, KRAS and NRAS mutations have been identified as biomarkers of resistance to these drugs, improving the selection of patients who might derive a benefit from these treatments. Nevertheless, several other alterations might affect the response to these drugs, and unfortunately, even the responders eventually become resistant by developing secondary (or acquired) resistance in approximately 13-18 mo. Several studies highlighted that the landscape of responsible alterations of both primary and acquired resistance to anti-EGFR drugs biochemically converge into MEK-ERK and PIK3CA-AKT pathways. In this review, we describe the currently known mechanisms of primary and acquired resistance to anti-EGFR moAbs together with the various strategies evaluated to prevent, overcame or revert them.

Patient considerations in metastatic colorectal cancer – role of panitumumab

“…A sizable percentage of CRC patients will be candidates for targeted therapy as 20%–25% present with metastatic disease, while another 20%–35% develop recurrence following curative early stage treatment 5,8–10. Metastatic disease has a median overall survival (OS) at ~30 months 11.…”

“…EGFR overexpression is seen in 60%–80% of CRC patients, making EGFR mAb inhibition an attractive treatment option 2,5,16. EGFR mAbs, cetuximab and panitumumab, inhibit EGFR by binding to the extracellular ligand-binding domain to compete with these endogenous ligands from binding 1,4,5,15,16.…”

“…Subtle differences in cetuximab and panitumumab’s mechanisms exist. Panitumumab has a higher binding affinity than cetuximab 3,5,16. However, cetuximab’s mechanism of action is thought to additionally have an immunologic-mediated response with antibody-dependent cellular toxicity due to cetuximab’s IgG 1 chimeric mAb structure.…”

¿Existen ventajas clínicas al evaluar el estado de los genes KRAS, NRAS, BRAF, PIK3CA, PTEN y HER2 en pacientes con cáncer colorrectal?

“…Es por eso que, en busca de una evaluación biomolecular más específica y profunda, en los ensayos clínicos se ha incluido la valoración de diferentes genes implicados en su oncogénesis, como KRAS, NRAS, BRAF, PIK3CA, PETEN y HER2; al igual que el estado de reparación del mal apareamiento del ADN [47][48][49][50][51] . Esta estratificación molecular permite agrupar o individualizar a los pacientes para un óptimo tratamiento de su enfermedad.…”

“…De otro lado, el impacto pronóstico del estado de BRAF sigue siendo controvertido 102,103 . Sin embargo, las investigaciones continúan para lograr afinar la utilidad clínica de estos biomarcadores [47][48][49]104 , ya que los estudios existentes han demostrado que entre los pacientes con cáncer colorrectal avanzado con el gen KRAS en estado nativo y que albergan mutaciones en los genes de NRAS, BRAF, PIK3CA, o PTEN, se puede demostrar resistencia al tratamiento con mAbs-EGFR 105 . …”