2024-01-22 ワシントン州立大学(WSU)
◆ジシクロミンと呼ばれる既存の薬物でCHRM1をブロックすると、ドセタキセルの効果が復元され、前立腺がんの細胞死と腫瘍成長の停止が観察されました。
◆ジシクロミンは既に市販されており、臨床利用が可能であるため、即座に患者への適用が期待されています。これにより前立腺がん患者の治療法が向上し、寿命の延長が期待されます。
<関連情報>
- https://news.wsu.edu/press-release/2024/01/22/protein-discovery-could-help-solve-prostate-cancer-drug-resistance/
- https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(23)00617-1
ムスカリンM1受容体を介したコリン作動性シグナル伝達が前立腺がんにおけるドセタキセル耐性をもたらす Cholinergic signaling via muscarinic M1 receptor confers resistance to docetaxel in prostate cancer Cell Reports Medicine Published:January 22, 2024 DOI:https://doi.org/10.1016/j.xcrm.2023.101388
Highlights
•CHRM1 is activated in CRPC cells upon acquisition of resistance to docetaxel
•CHRM1 is elevated in tumor tissues from prostate cancer patients after chemotherapy
•CHRM1 interacts with cMET to induce a polykinase program for docetaxel resistance
•CHRM1 inhibitor dicyclomine treatment overcomes docetaxel resistance
Summary
Docetaxel is the most commonly used chemotherapy for advanced prostate cancer (PC), including castration-resistant disease (CRPC), but the eventual development of docetaxel resistance constitutes a major clinical challenge. Here, we demonstrate activation of the cholinergic muscarinic M1 receptor (CHRM1) in CRPC cells upon acquiring resistance to docetaxel, which is manifested in tumor tissues from PC patients post- vs. pre-docetaxel. Genetic and pharmacological inactivation of CHRM1 restores the efficacy of docetaxel in resistant cells. Mechanistically, CHRM1, via its first and third extracellular loops, interacts with the SEMA domain of cMET and forms a heteroreceptor complex with cMET, stimulating a downstream mitogen-activated protein polykinase program to confer docetaxel resistance. Dicyclomine, a clinically available CHRM1-selective antagonist, reverts resistance and restricts the growth of multiple docetaxel-resistant CRPC cell lines and patient-derived xenografts. Our study reveals a CHRM1-dictated mechanism for docetaxel resistance and identifies a CHRM1-targeted combinatorial strategy for overcoming docetaxel resistance in PC.
Graphical abstract
