Targeting CD44v6 and PI3K disrupts HGF-driven reprogramming of colorectal cancer stem cells

Abstract

Therapeutic adaptive responses and secondary resistance represent major obstacles to effective colorectal cancer treatment. These dynamic adaptations arise within a permissive tumor microenvironment that sustains cancer cell survival, epithelial-mesenchymal plasticity and the outgrowth of drug-tolerant clones, ultimately driving disease progression and poor patient outcomes. Here, it is shown that AMC303, a highly selective CD44v6 inhibitor, needs to be combined with a PI3K/mTOR inhibitor to prevent or reverse anti-tumor therapeutic resistance and disease progression under tumor microenvironmental cues. Cytokines released by tumor-associated cells, such as HGF, induce c-Met phosphorylation, CD44v6 expression and enhanced clonogenicity, thereby expanding cancer stem cell populations that undergo transcriptional reprogramming towards a hybrid EMT state with increased resistance and metastatic potential. In colorectal cancer stem cell mouse avatars, HGF promotes phenotypic reprogramming even when canonical CD44v6/c-Met signaling is blocked by AMC303, acting instead through c-Met co-receptors and downstream PI3K/AKT and MAPK pathways. By suppressing compensatory PI3K/AKT and MAPK signaling, the addition of Apitolisib, the dual PI3K/mTOR inhibitor, reduces the proliferation rate and makes cancer cells more vulnerable to the in vitro exposure with standard chemotherapeutic regimen. Collectively, these findings support a therapeutic strategy that targets key molecular mechanisms underlying cancer cell reprogramming, adaptive therapeutic escape and the emergence of aggressive colorectal cancer phenotypes.