Inhibition of WNT signaling sensitizes CRC cells to anti-tumor effects of retinoids: basis for new drug combinations in oncology.
- 1Cawley Center for Translational Cancer Research, Helen F. Graham Cancer Center & Research Institute, Newark, DE, USA.
- 2Department of Biological Sciences, University of Delaware, Newark, DE, USA.
- 3Department of Pharmacology & Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA, USA.
Abstract
Our Goal is to sensitize human colorectal cancer (CRC) to the differentiation-inducing effects of retinoic acid (RA) agents by suppressing WNT signaling. Previously, we reported that the WNT and RA pathways are functionally linked, and in CRC, APC mutation generates a WNT:RA imbalance leading to incomplete differentiation and stem cell (SC) overpopulation. Hypothesis: Therapeutically inhibiting WNT signaling enhances the ability of retinoid agents to induce growth suppression and differentiation. We tested drug combinations of: (1) anti-WNT agents (Sulindac & Piroxicam) that produce anti-tumor activity in humans and animals harboring germline APC mutations, with (2) RA agents (All-trans-RA, 9-cis RA) and RA metabolism blocking agent (CYP26A1 inhibitors Liarozole and Talarozole), which inhibit proliferation and induce differentiation of CRC cell lines. Results: The combined effect of anti-WNT agents and RA drugs shows additive or synergistic responses in CRC cell lines compared to single agents. Drug combinations decrease the proportion of aldehyde dehydrogenase-positive SCs and increase neuroendocrine cell differentiation in CRC cells that show a synergistic response to treatment. NanoString profiling shows that therapeutically decreasing WNT signaling in CRC cells significantly changes the effect of RA signaling on gene expression. Treating human CRC organoid cultures and PDX mouse models with WNT:RA-based drug combinations led to greater anti-tumor activity as compared to individual agents. Conclusion: Inhibiting WNT signaling effectively sensitizes CRC cells to the anti-tumor effects of retinoids. These findings have important clinical significance for designing new drug combinations against CRC.
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BibTeX
@article{hunsu2026inhibition,
title = {{Inhibition of WNT signaling sensitizes CRC cells to anti-tumor effects of retinoids: basis for new drug combinations in oncology.}},
author = {Victoria O Hunsu and Caroline O B Facey and Lynn M Opdenaker and Bruce M Boman},
journal = {Cancer biology \& therapy},
year = {2026},
month = oct,
doi = {10.1080/15384047.2026.2732738},
url = {https://europepmc.org/article/MED/42845214},
note = {CC BY},
}
RIS
TY - JOUR
TI - Inhibition of WNT signaling sensitizes CRC cells to anti-tumor effects of retinoids: basis for new drug combinations in oncology.
AU - Victoria O Hunsu
AU - Caroline O B Facey
AU - Lynn M Opdenaker
AU - Bruce M Boman
PY - 2026
DA - 2026/10/08
JO - Cancer biology & therapy
DO - 10.1080/15384047.2026.2732738
UR - https://europepmc.org/article/MED/42845214
AB - Our Goal is to sensitize human colorectal cancer (CRC) to the differentiation-inducing effects of retinoic acid (RA) agents by suppressing WNT signaling. Previously, we reported that the WNT and RA pathways are functionally linked, and in CRC, APC mutation generates a WNT:RA imbalance leading to incomplete differentiation and stem cell (SC) overpopulation. Hypothesis: Therapeutically inhibiting WNT signaling enhances the ability of retinoid agents to induce growth suppression and differentiation. We tested drug combinations of: (1) anti-WNT agents (Sulindac & Piroxicam) that produce anti-tumor activity in humans and animals harboring germline APC mutations, with (2) RA agents (All-trans-RA, 9-cis RA) and RA metabolism blocking agent (CYP26A1 inhibitors Liarozole and Talarozole), which inhibit proliferation and induce differentiation of CRC cell lines. Results: The combined effect of anti-WNT agents and RA drugs shows additive or synergistic responses in CRC cell lines compared to single agents. Drug combinations decrease the proportion of aldehyde dehydrogenase-positive SCs and increase neuroendocrine cell differentiation in CRC cells that show a synergistic response to treatment. NanoString profiling shows that therapeutically decreasing WNT signaling in CRC cells significantly changes the effect of RA signaling on gene expression. Treating human CRC organoid cultures and PDX mouse models with WNT:RA-based drug combinations led to greater anti-tumor activity as compared to individual agents. Conclusion: Inhibiting WNT signaling effectively sensitizes CRC cells to the anti-tumor effects of retinoids. These findings have important clinical significance for designing new drug combinations against CRC.
SN - 1538-4047
SN - 1555-8576
ER -