Genomic Alterations in <i>PIK3CA</i>-Mutated Breast Cancer Result in mTORC1 Activation and Limit the Sensitivity to PI3Kα Inhibitors

Xu, Guotai; Wu, Fan; Michelini, Flavia; Chan, Carmen Wing Han; Qu, Xuan; Selenica, Pier; Ladewig, Erik; Castel, Pau; Cheng, Yuanming; Zhao, Alison; Jhaveri, Komal; Toska, Eneda; Jimenez, Marta; Jacquet, Alexandra; Tran-Dien, Alicia; André, Fabrice; Chandarlapaty, Sarat; Reis‐Filho, Jorge S.; Razavi, Pedram; Scaltriti, Maurizio

doi:10.1158/0008-5472.can-20-3232

Cited by 22 publications

(15 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The TSC1-TSC2 complex is a critical negative regulator of mTORC1 signaling [ 36 ]. Given that TSC1 and TSC2 were identified as the strongest drivers of AKT inhibitor resistance in our CRISPR screen, and the TSC1-2 complex has previously been associated with PI3Kα inhibitor resistance [ 37 , 38 ], the regulation of mTORC1 signaling by this complex appears to be a dominant driver of resistance to PI3K/AKT inhibition. Resistance to PI3Kβ inhibition was conferred by two PI3K signaling related genes INPPL1 (encoding SHIP2 protein) and PIK3R2 (encoding P85β protein).…”

Section: Resultsmentioning

confidence: 99%

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

Dunn

Eberlein²,

Yu³

et al. 2022

Oncogene

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

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

Dunn

Eberlein²,

Yu³

et al. 2022

Oncogene

View full text Add to dashboard Cite

show abstract

“…MTORC2 is the "upstream" of Akt, which directly phosphorylates Akt and participates in the regulation of the cytoskeleton (Cirone, 2021). Inhibition of mTORC1 can result in the activation of the PI3K pathway (Cai et al, 2021). This can be attributed to the negative feedback from mTORC2 that results in the phosphorylation of Akt (Amin et al, 2021).…”

Section: Downstream Target Akt Of Pi3kmentioning

confidence: 99%

Research Progress on the Regulation Mechanism of Key Signal Pathways Affecting the Prognosis of Glioma

Wei

et al. 2022

Front. Mol. Neurosci.

View full text Add to dashboard Cite

As is known to all, glioma, a global difficult problem, has a high malignant degree, high recurrence rate and poor prognosis. We analyzed and summarized signal pathway of the Hippo/YAP, PI3K/AKT/mTOR, miRNA, WNT/β-catenin, Notch, Hedgehog, TGF-β, TCS/mTORC1 signal pathway, JAK/STAT signal pathway, MAPK signaling pathway, the relationship between BBB and signal pathways and the mechanism of key enzymes in glioma. It is concluded that Yap1 inhibitor may become an effective target for the treatment of glioma in the near future through efforts of generation after generation. Inhibiting PI3K/Akt/mTOR, Shh, Wnt/β-Catenin, and HIF-1α can reduce the migration ability and drug resistance of tumor cells to improve the prognosis of glioma. The analysis shows that Notch1 and Sox2 have a positive feedback regulation mechanism, and Notch4 predicts the malignant degree of glioma. In this way, notch cannot only be treated for glioma stem cells in clinic, but also be used as an evaluation index to evaluate the prognosis, and provide an exploratory attempt for the direction of glioma treatment. MiRNA plays an important role in diagnosis, and in the treatment of glioma, VPS25, KCNQ1OT1, KB-1460A1.5, and CKAP4 are promising prognostic indicators and a potential therapeutic targets for glioma, meanwhile, Rheb is also a potent activator of Signaling cross-talk etc. It is believed that these studies will help us to have a deeper understanding of glioma, so that we will find new and better treatment schemes to gradually conquer the problem of glioma.

show abstract

“…Overexpression of NPRL2 in colon cancer cells increases the sensitivity to a topoisomerase I inhibitor irinotecan (CPT-11) by activation of the DNA damage checkpoints [207]. Genomic alternations of all three GATOR1 components have recently been associated with the resistance to PI3Kα inhibitors in primary and metastatic breast cancer [208]. This resistance is explained by the sustained activation of the mTORC1 pathway due to the loss of function mutations of GATOR1 components.…”

Section: Cancer and Anticancer Drug Resistance-nprl2 And Othersmentioning

confidence: 99%

SEA and GATOR 10 Years Later

Loissell-Baltazar

Dokudovskaya

2021

Cells

View full text Add to dashboard Cite

The SEA complex was described for the first time in yeast Saccharomyces cerevisiae ten years ago, and its human homologue GATOR complex two years later. During the past decade, many advances on the SEA/GATOR biology in different organisms have been made that allowed its role as an essential upstream regulator of the mTORC1 pathway to be defined. In this review, we describe these advances in relation to the identification of multiple functions of the SEA/GATOR complex in nutrient response and beyond and highlight the consequence of GATOR mutations in cancer and neurodegenerative diseases.

show abstract

Genomic Alterations in PIK3CA-Mutated Breast Cancer Result in mTORC1 Activation and Limit the Sensitivity to PI3Kα Inhibitors

Cited by 22 publications

References 50 publications

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

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

Research Progress on the Regulation Mechanism of Key Signal Pathways Affecting the Prognosis of Glioma

SEA and GATOR 10 Years Later

Contact Info

Product

Resources

About