AKT-mTORC1 reactivation is the dominant resistance driver for PI3Kβ/AKT inhibitors in PTEN-null breast cancer and can be overcome by combining with Mcl-1 inhibitors

被引：23

作者：

Dunn, Shanade ^{[1
,2
]}

Eberlein, Cath ^{[3
]}

Yu, Jason ^{[1
,7
]}

Gris-Oliver, Albert ^{[4
]}

Ong, Swee Hoe ^{[1
]}

Yelland, Urs ^{[3
]}

Cureton, Natalie ^{[3
]}

Staniszewska, Anna ^{[2
]}

McEwen, Robert ^{[2
]}

Fox, Millie ^{[2
]}

Pilling, James ^{[5
]}

Hopcroft, Philip ^{[5
]}

Coker, Elizabeth A. ^{[1
]}

Jaaks, Patricia ^{[1
]}

Garnett, Mathew J. ^{[1
]}

Isherwood, Beverley ^{[5
]}

Serra, Violeta ^{[4
]}

Davies, Barry R. ^{[2
]}

Barry, Simon T. ^{[2
]}

Lynch, James T. ^{[2
]}

Yusa, Kosuke ^{[1
,6
]}

机构：

[1] Wellcome Sanger Inst, Cambridge, England

[2] AstraZeneca, Early Oncol, Biosci, Cambridge, England

[3] AstraZeneca, Early Oncol, Biosci, Alderley Pk, England

[4] Vall dHebron Inst Oncol, Barcelona, Spain

[5] AstraZeneca, Discovery Sci, Cambridge, England

[6] Kyoto Univ, Inst Frontier Life & Med Sci, Kyoto, Japan

[7] Francis Crick Inst, Mol Biol Metab Lab, London, England

来源：

ONCOGENE | 2022年 / 41卷 / 46期

基金：

英国惠康基金;

关键词：

AKT INHIBITOR; TUMORS; PI3K-ALPHA; COMBINATION; DISCOVERY; PATHWAY; MTORC1; CAPIVASERTIB; MULTICENTER; FULVESTRANT;

D O I：

10.1038/s41388-022-02482-9

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The PI3K pathway is commonly activated in breast cancer, with PI3K-AKT pathway inhibitors used clinically. However, mechanisms that limit or enhance the therapeutic effects of PI3K-AKT inhibitors are poorly understood at a genome-wide level. Parallel CRISPR screens in 3 PTEN-null breast cancer cell lines identified genes mediating resistance to capivasertib (AKT inhibitor) and AZD8186 (PI3K beta inhibitor). The dominant mechanism causing resistance is reactivated PI3K-AKT-mTOR signalling, but not other canonical signalling pathways. Deletion of TSC1/2 conferred resistance to PI3K beta i and AKTi through mTORC1. However, deletion of PIK3R2 and INPPL1 drove specific PI3K beta i resistance through AKT. Conversely deletion of PIK3CA, ERBB2, ERBB3 increased PI3K beta i sensitivity while modulation of RRAGC, LAMTOR1, LAMTOR4 increased AKTi sensitivity. Significantly, we found that Mcl-1 loss enhanced response through rapid apoptosis induction with AKTi and PI3K beta i in both sensitive and drug resistant TSC1/2 null cells. The combination effect was BAK but not BAX dependent. The Mcl-1i + PI3K beta/AKTi combination was effective across a panel of breast cancer cell lines with PIK3CA and PTEN mutations, and delivered increased anti-tumor benefit in vivo. This study demonstrates that different resistance drivers to PI3K beta i and AKTi converge to reactivate PI3K-AKT or mTOR signalling and combined inhibition of Mcl-1 and PI3K-AKT has potential as a treatment strategy for PI3K beta i/AKTi sensitive and resistant breast tumours.

引用

页码：5046 / 5060

页数：15

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