Reference Detail

Ref Type

Journal Article

PMID

(36241868)

Authors

Dunn S, Eberlein C, Yu J, Gris-Oliver A, Ong SH, Yelland U, Cureton N, Staniszewska A, McEwen R, Fox M, Pilling J, Hopcroft P, Coker EA, Jaaks P, Garnett MJ, Isherwood B, Serra V, Davies BR, Barry ST, Lynch JT, Yusa K

Title

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Oncogene	41	46	2022 Nov	5046-5060	Oncogene

URL

Abstract Text

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 (PI3Kβ 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 PI3Kβi and AKTi through mTORC1. However, deletion of PIK3R2 and INPPL1 drove specific PI3Kβi resistance through AKT. Conversely deletion of PIK3CA, ERBB2, ERBB3 increased PI3Kβi 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 PI3Kβi in both sensitive and drug resistant TSC1/2 null cells. The combination effect was BAK but not BAX dependent. The Mcl-1i + PI3Kβ/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 PI3Kβi 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 PI3Kβi/AKTi sensitive and resistant breast tumours.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PTEN inact mut	breast cancer	predicted - sensitive	AZD5991 + Capivasertib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the combination of AZD5991 and Truqap (capivasertib) synergistically inhibited proliferation and induced apoptosis in a triple-negative breast cancer cell line and hormone-receptor positive breast cancer cell line each harboring a PTEN inactivating mutation in culture and inhibited tumor growth in cell line xenograft models (PMID: 36241868).	36241868
PTEN inact mut	breast cancer	predicted - sensitive	AZD5991 + AZD8186	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the combination of AZD5991 and AZD8186 synergistically inhibited proliferation and induced apoptosis in a triple-negative breast cancer cell line and hormone receptor-positive breast cancer cell line each harboring a PTEN inactivating mutation in culture and inhibited tumor growth in cell line xenograft models (PMID: 36241868).	36241868