• drug resistance
• colorectal cancer
• stem cells

With over 900 000 deaths per year worldwide in 2020 according to Globocan, colorectal cancer (CRC) represents the third deadliest cancer. Over the past 20 years, the median overall survival for CRC has substantially increased, especially in patients with metastatic disease, which has doubled to reach 30 months, as a result of the advent of targeted therapies. Despite this progress, the 5-year survival rate for patients with metastatic CRC remains below 15%, calling for an improved management of these patients, which account for roughly 20%–30% of new diagnosed cases.

A consensus view is that CRC arises from uncontrolled expansion of intestinal stem cells (ISCs).1 By analogy with ISCs, CRC stem cells (CSCs) are endowed with self-renewal potential and display significant plasticity. They are believed to fuel CRC growth as well as metastasis, and display resistance to therapy, making their targeting one of the most critical challenges in the field of oncology.1 The study by Mangiapane et al 2 tackles this issue by leveraging a collection of colorectal CSCs growing as spheroids and expressing the CSC marker CD44v6, which they previously showed to define a population of CSCs with enhanced metastatic potential.3 Among those, some bear RAS or BRAF mutations and were thoroughly resistant to the anti-epidermal growth factor receptor (EGFR) antibody cetuximab, as anticipated. Unexpectedly, a significant proportion of RAS and BRAF wild-type CSCs also displayed resistance …