The quest to overcome resistance to EGFR-targeted therapies in cancer

Abstract

All patients with metastatic lung, colorectal, pancreatic or head and neck cancers who initially benefit from epidermal growth factor receptor (EGFR)-targeted therapies eventually develop resistance. An increasing understanding of the number and complexity of resistance mechanisms highlights the Herculean challenge of killing tumors that are resistant to EGFR inhibitors. Our growing knowledge of resistance pathways provides an opportunity to develop new mechanism-based inhibitors and combination therapies to prevent or overcome therapeutic resistance in tumors. We present a comprehensive review of resistance pathways to EGFR-targeted therapies in lung, colorectal and head and neck cancers and discuss therapeutic strategies that are designed to circumvent resistance.

Figure 1

EGFR signaling pathways. Activation of EGFR leads to downstream signaling pathways that ultimately drive tumor proliferation or impair apoptosis. These pathways mediate resistance through crosstalk or inappropriate activation but also provide targets for drugs to overcome resistance. IGFR, insulin-like growth factor receptor; PLC, phospholipase C; GAS6, growth arrest-specific 6.

Figure 2

Timeline of key discoveries in the EGFR field. The timeline charts important findings from basic and clinical research into EGFR and its role in cancer^{,,,,,,,,,,,,–} (adapted from ref. 153). FDA, US Food and Drug Administration; OS, overall survival; CTCs, circulating tumor cells; SCLC, small cell lung cancer; iPASS, Iressa Pan-Asia Study.

Figure 3

Clinically validated resistance mechanisms to EGFR inhibitors. Treatment with EGFR-targeted therapy results in tumor responses, which are blunted by the selection or evolution of clones with resistant EGFR (T790M or S492R), oncogenic shift (activation, upregulation or amplification of a bypass pathway), inhibition of apoptosis or histologic transformation (figure adapted from ref. 79).

Figure 4

Efficacy of targeted therapies in cancer treatment. Response rates and impact on progression-free survival vary widely among targeted therapies. The orange oval represents the reported response rates and progression-free survival for EGFR TKIs in EGFR-mutant lung adenocarcinoma (adapted from Supplementary Table 1). Imatinib targets BCR–ABL, has a ~95% response rate and has turned CML into a chronic disease for many patients. All-trans retinoic acid targets the PML–RAR fusion protein and may cure acute promyelocytic leukemia (APML) when given in combination with chemotherapy. For solid tumors such as melanoma and lung cancer, targeted therapies have a lower response rate and less of an impact on progression-free survival^–. GIST, gastrointestinal stromal tumors.