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.
Authors
- Francesco Verona (ORCID: https://orcid.org/0000-0001-6226-4624)
- Irene Pillitteri (ORCID: https://orcid.org/0000-0002-8013-218X)
- Veronica Veschi (ORCID: https://orcid.org/0000-0002-6379-7366)
- Vincenzo Davide Pantina (ORCID: https://orcid.org/0000-0003-1144-0434)
- Alice Turdo (ORCID: https://orcid.org/0000-0002-6152-4903)
- Simone Di Franco (ORCID: https://orcid.org/0000-0002-6217-2161)
- Chiara Modica (ORCID: https://orcid.org/0000-0002-7000-5216)
- Ornella Roberta Brancato (ORCID: https://orcid.org/0000-0002-2783-0720)
- Miriam Gaggianesi (ORCID: https://orcid.org/0000-0002-7810-856X)
- Kimiya Shams
- Caterina D’Accardo (ORCID: https://orcid.org/0000-0003-1171-8678)
- Paola Bianca (ORCID: https://orcid.org/0000-0002-9172-0809)
- Matilde Todaro (ORCID: https://orcid.org/0000-0001-8686-8043)
- Gaetana Porcelli (ORCID: https://orcid.org/0000-0002-7991-407X)
- Giorgio Stassi (ORCID: https://orcid.org/0000-0002-1016-9059)
- Laura Rosa Mangiapane (ORCID: https://orcid.org/0000-0003-4186-0157)
- Ilio Vitale (ORCID: https://orcid.org/0000-0002-5918-1841)
- Sebastiano Di Bella (ORCID: https://orcid.org/0000-0001-7161-303X)
- Klaus Dembowsky
- Kiyotsugu Yoshikawa (ORCID: https://orcid.org/0009-0001-2186-4313)
- Noemi di Miceli (ORCID: https://orcid.org/0009-0009-1151-4019)
- Laurie Clauzon
- Francesco Orilio
Institutions
- Italian institute for Genomic Medicine (IT)
- Candiolo Cancer Institute (IT)
- Doshisha Women's College of Liberal Arts (JP)
- Sapienza University of Rome (IT)
- University of Palermo (IT)
- Technische Universität Braunschweig (DE)
Publication Details
- Journal
- Cell Death Discovery
- Published
- 2026-10-26
- DOI
- https://doi.org/10.1038/s41420-026-03408-0
- Primary Topic
- Cancer Cells and Metastasis
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- European Commission
- Ministero della Salute
- Associazione Italiana per la Ricerca sul Cancro
- HORIZON EUROPE Framework Programme
- NextGenerationEU