Targeting EGFR pathway in metastatic colorectal cancer- tumour heterogeniety and convergent evolution

•Targeting EGFR pathway with mAbs in selected mCRC patients is a well-established treatment strategy.•Resistance to anti-EGFR therapies is however inevitable.•ITH and polyclonal resistance mechanisms under selective pressure of anti-EGFR therapies are likely to influence the biological and clinical behaviour of cancer cells.•Prospective tissue collection within PROSPECT-C study allowed authors to enhance the understanding about mechanisms of resistance to anti-EGFR therapies.•This review describes the development of anti-EGFR therapies in mCRC with emphasis on the validation and description of known and novel resistance mechanisms respectively. Despite significant progress in management of metastatic colorectal cancer (mCRC) pertaining to better screening procedures and amelioration of the therapeutic armamentarium with targeted therapies, prognosis remains poor. Targeting epidermal growth factor receptor (EGFR) has been of particular interest owing to favourable efficacy benefits demonstrated by monoclonal antibodies (cetuximab and panitumumab) in various clinical settings and development of predictive biomarkers informing treatment decisions respectively. In spite of optimal patient selection based on RAS mutation status, primary and secondary resistance to monoclonal antibodies is higher than desired. Further research into predictive biomarkers is therefore essential, but has, to date, been conducted with considerable limitations. Whilst molecular heterogeneity has been demonstrated by several studies in mCRC, for incomprehensible reasons, multiple resistant genetic alterations that emerge under the selective pressure of EGFR-targeted therapies are somehow able to influence the biological and clinical behaviour of cancer cells, despite being detectable at extremely low frequencies. Intriguingly, these subclonal events largely seem to converge on RAS/RAF/MAPK pathway in patients treated with EGFR-targeted monoclonal antibodies. This review describes the clinical and biological evolution and development of EGFR targeted therapies in mCRC, the challenges in the presence of molecular complexities, the role of cell free (cf)-DNA and future strategies that could lead to further optimal discovery of clinically meaningful biomarkers and application of precision medicine.