The allosteric IDH1 inhibitor ivosidenib overcomes chemoresistance in intrahepatic cholangiocarcinoma models expressing wild-type IDH1 - PubMed
3 hours ago
- #chemoresistance
- #cholangiocarcinoma
- #IDH1
- Gemcitabine-based chemotherapy is standard for advanced intrahepatic cholangiocarcinoma (iCCA), but chemoresistance limits efficacy.
- IDH1 was identified as a key target conferring chemoresistance to gemcitabine in iCCA using a CRISPR/Cas9 library.
- IDH1 knockdown or pharmacological inhibition (e.g., ivosidenib) enhanced gemcitabine efficacy in wild-type IDH1 (wtIDH1) iCCA models.
- wtIDH1 maintains redox homeostasis by generating α-ketoglutarate and NADPH, protecting cells from gemcitabine-induced oxidative stress.
- Ivosidenib synergizes with gemcitabine by boosting oxidative stress in wtIDH1 iCCA models.
- Low Mg2+ levels in the iCCA tumor microenvironment enhance ivosidenib's therapeutic window.
- Combining IDH1 inhibition with chemotherapy shows promise for wtIDH1 iCCA and other tumors.