Mechanisms of resistance to anti-EGFR therapy in colorectal cancer

Abstract

Targeting the epidermal growth factor receptor (EGFR) either alone or in combination with chemotherapy is effective for patients with RAS wild type metastatic colorectal cancer (mCRC). However, only a small percentage of mCRC patients are sensitive to anti-EGFR therapy and even the best cases finally become refractory to this therapy. It has become apparent that the RAS mutations correlate with resistance to anti-EGFR therapy. However, these resistance mechanisms only account for nearly 35% to 50% of nonresponsive patients, suggesting that there might be additional mechanisms. In fact, several novel pathways leading to escape from anti-EGFR therapy have been reported in recent years. In this review, we provide an overview of known and novel mechanisms that contribute to both primary and acquired anti-EGFR therapy resistance, and enlist possible treatment strategies to overcome or reverse this resistance.

Keywords: acquired resistance; colorectal cancer; epidermal growth factor receptor; primary resistance; targeted drug.

Figure 1. EGFR-mediated signaling pathways and mechanisms of anti-EGFR therapy

EGFR ligands bind the extracellular domain of EGFR, lead receptor activation and stimulate downstream signaling pathways that are crucial for cell growth and proliferation. Cetuximab or Panitumumab prevents ligand binding to EGFR, thus blocking EGFR signaling.

Figure 2. Aberrated genetic alterations in the members of EGFR signaling pathways induce resistance to anti-EGFR therapy

Aberrated genetic alterations, including RAS, BRAF, PIK3CA, EGFR S492R mutations, PTEN loss, and STAT3 phosphorylation contribute to the resistance through constitutive activation of EGFR downstream signaling cascades regardless of EGFR blockade. The molecules implicated in EGFR signaling and affected by resistant alterations are highlighted in special colors and described in note.

Figure 3. Aberrated activations of the bypass pathways induce resistance to anti-EGFR therapy

EGFR downstream effectors can be activated by alternative and/or compensatory membrane growth factors, includingIGF-1R, MET, HER2, and VEGFR. These growth factors then trigger intracellular signaling pathways bypassing EGFR and induce tumour cell growth and proliferation, and lead resistance to anti-EGFR therapy.