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

• Published in: Oncogene Vol. 41; no. 46; pp. 5046 - 5060
• Main Authors: Dunn, Shanade, Eberlein, Cath, Yu, Jason, Gris-Oliver, Albert, Ong, Swee Hoe, Yelland, Urs, Cureton, Natalie, Staniszewska, Anna, McEwen, Robert, Fox, Millie, Pilling, James, Hopcroft, Philip, Coker, Elizabeth A, Jaaks, Patricia, Garnett, Mathew J, Isherwood, Beverley, Serra, Violeta, Davies, Barry R, Barry, Simon T, Lynch, James T, Yusa, Kosuke
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 11.11.2022; Nature Publishing Group UK
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Antineoplastic Agents - pharmacology; Apoptosis; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Cell Line, Tumor; Class I Phosphatidylinositol 3-Kinases - genetics; CRISPR; Drug resistance; ErbB-2 protein; ErbB-3 protein; Female; Genomes; Guanine Nucleotide Exchange Factors; Humans; Inositol polyphosphate 5-phosphatase; Mcl-1 protein; Mechanistic Target of Rapamycin Complex 1; Null cells; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - metabolism; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; PTEN protein; Signal transduction; TOR protein; TOR Serine-Threonine Kinases - metabolism; Tuberous Sclerosis Complex 1; Tumor cell lines; Tumors
• ISSN: 0950-9232; 1476-5594; 1476-5594
• DOI: 10.1038/s41388-022-02482-9

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.