再発急性骨髄性白血病におけるがん治療抵抗性との闘い(Battling cancer treatment resistance in relapsed acute myeloid leukaemia)

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2024-04-05 シンガポール国立大学(NUS)

再発急性骨髄性白血病におけるがん治療抵抗性との闘い(Battling cancer treatment resistance in relapsed acute myeloid leukaemia)

シンガポール国立大学薬学部のShruti Bhatt助教授率いる科学者チームが、急性骨髄性白血病(AML)と呼ばれる激しい血液がんの治療耐性の原因としてアポトーシスの回避を明らかにしました。この獲得抵抗メカニズムを標的とすることで、AMLの再発患者の効果的な治療薬の同定に寄与することが期待されています。彼らは、動的BH3プロファイリング(DBP)と呼ばれる手法の効果も示し、再発した白血病細胞をターゲットにする抗がん薬の同定に役立つ可能性があることを強調しました。

<関連情報>

急性骨髄性白血病における後天性多剤耐性は、再発骨髄芽細胞におけるアポトーシス・プライミングの低下によって引き起こされる Acquired Multidrug Resistance in AML Is Caused by Low Apoptotic Priming in Relapsed Myeloblasts

Elyse A. Olesinski;Karanpreet Singh Bhatia;Chuqi Wang;Marissa S. Pioso;Xiao Xian Lin;Ahmed M. Mamdouh;Shu Xuan Ng;Vedant Sandhu;Shaista Shabbir Jasdanwala;Binyam Yilma;Stephan Bohl;Jeremy A. Ryan;Disha Malani;Marlise R. Luskin;Olli Kallioniemi;Kimmo Porkka;Sophia Adamia;Wee Joo Chng;Motomi Osato;David M. Weinstock;Jacqueline S. Garcia;Anthony Letai;Shruti Bhatt
Blood Cancer Discovery  Published:March 04 2024
DOI:https://doi.org/10.1158/2643-3230.BCD-24-0001

Abstract

In many cancers, mortality is associated with the emergence of relapse with multidrug resistance (MDR). Thus far, the investigation of cancer relapse mechanisms has largely focused on acquired genetic mutations. Using acute myeloid leukemia (AML) patient-derived xenografts (PDX), we systematically elucidated a basis of MDR and identified drug sensitivity in relapsed AML. We derived pharmacologic sensitivity for 22 AML PDX models using dynamic BH3 profiling (DBP), together with genomics and transcriptomics. Using in vivo acquired resistant PDXs, we found that resistance to unrelated, narrowly targeted agents in distinct PDXs was accompanied by broad resistance to drugs with disparate mechanisms. Moreover, baseline mitochondrial apoptotic priming was consistently reduced regardless of the class of drug-inducing selection. By applying DBP, we identified drugs showing effective in vivo activity in resistant models. This study implies evasion of apoptosis drives drug resistance and demonstrates the feasibility of the DBP approach to identify active drugs for patients with relapsed AML.

Significance:
Acquired resistance to targeted therapy remains challenging in AML. We found that reduction in mitochondrial priming and common transcriptomic signatures was a conserved mechanism of acquired resistance across different drug classes in vivo. Drugs active in vivo can be identified even in the multidrug resistant state by DBP.

医療・健康
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