Journal
CELLS
Volume 11, Issue 22, Pages -Publisher
MDPI
DOI: 10.3390/cells11223663
Keywords
regorafenib; CRC; phenotype switch; senescence; EMT
Categories
Funding
- Fund for Scientific Research (FNRS-Televie)
- Les Amis de l'Institut Bordet
- La Fondation Rose et Jean Hoguet
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This study explores potential resistance mechanisms to regorafenib in CRC cells. Short-term exposure led to senescence-like features, while long-term exposure resulted in acquired resistance. Different cell lines displayed different senescence states and phenotype changes. HCT-116 cells acquired a more aggressive phenotype through EMT, while SW480 cells showed cell arrest and senescence features.
Potential intrinsic resistance mechanisms to regorafenib were explored after short exposure (3 days) on five CRC cell lines (HCT-116, SW1116, LS-1034, SW480, Caco-2). The observation of senescence-like features led to the investigation of a drug-initiated phenotype switch. Following long-term exposure (12 months) of HCT-116 and SW480 cell lines to regorafenib, we developed resistant models to explore acquired resistance. SW480 cells demonstrated senescent-like properties, including a cell arrest in the late G2/prophase cell cycle stage and a statistically significant decrease in the expression of G1 Cyclin-Dependent Kinase inhibitors and key cell cycle regulators. A specific senescence-associated secretome was also observed. In contrast, HCT-116 treated cells presented early senescent features and developed acquired resistance triggering EMT and a more aggressive phenotype over time. The gained migration and invasion ability by long-exposed cells was associated with the increased expression level of key cellular and extracellular EMT-related factors. The PI3K/AKT pathway was a significant player in the acquired resistance of HCT-116 cells, possibly related to a PI3KCA mutation in this cell line. Our findings provide new insights into the phenotypic plasticity of CRC cells able, under treatment pressure, to acquire a stable TIS or to use an early senescence state to undergo EMT.
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