タンパク質発見が前立腺がん薬剤耐性の解決に役立つ可能性(Protein discovery could help solve prostate cancer drug resistance)

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2024-01-22 ワシントン州立大学(WSU)

◆ワシントン州立大学の研究者は、前立腺がん細胞のドセタキセルと呼ばれる一般的な化学療法薬に対する耐性に関与する受容体タンパク質「CHRM1」を発見し、これを阻害することで新しい治療戦略が可能かもしれないと示唆しました。
◆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>

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

タンパク質発見が前立腺がん薬剤耐性の解決に役立つ可能性(Protein discovery could help solve prostate cancer drug resistance)

有機化学・薬学
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