Phosphorylation of IDH1 Facilitates Progestin Resistance in Endometrial Cancer

The progestin regimen is one of the main therapeutic strategies for women with endometrial cancer who undergo conservative management. Although many patients respond well to initial therapy, progestin-refractory disease inevitably emerges, and the molecular basis underlying progestin resistance has not been comprehensively elucidated. Herein, they demonstrated progestin results in p38-dependent IDH1 Thr 77 phosphorylation (pT77-IDH1). pT77-IDH1 translocates into the nucleus and is recruited to chromatin through its interaction with OCT6. IDH1-produced alpha-ketoglutarate (alpha KG) then facilitates the activity of OCT6 to promote focal adhesion related target gene transcription to confer progestin resistance. Pharmacological inhibition of p38 or focal adhesion signaling sensitizes endometrial cancer cells to progestin in vivo. The study reveals p38-dependent pT77-IDH1 as a key mediator of progestin resistance and a promising target for improving the efficacy of progestin therapy. The study reports a previously unrecognized link between IDH1 T77 phosphorylation and progestin resistance in endometrial cancer. Progestin treatment leads to p38-dependent phosphorylation of IDH1 at threonine 77 (pT77-IDH1). pT77-IDH1-induced focal adhesion signaling creates therapeutic vulnerabilities in progestin resistance, and pharmacological blockage of pT77-IDH1 or focal adhesion has the potential to be translatable into the clinical setting. image