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Impact on the Sustainable Development Goals (SDGs)

Analysis of institutional authors

Gris-Oliver, AlbertAuthor
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AKT-mTORC1 reactivation is the dominant resistance driver for PI3K?/AKT inhibitors in PTEN-null breast cancer and can be overcome by combining with Mcl-1 inhibitors

Publicated to:Oncogene. 41 (46): 5046-5060 - 2022-01-01 41(46), DOI: 10.1038/s41388-022-02482-9

Authors: Shanade Dunn; Cath Eberlein; Jason Yu; Albert Gris‐Oliver; Swee Hoe Ong; Urs Yelland; Natalie Cureton; Anna D. Staniszewska; Robert McEwen; Millie Fox; James Pilling; Philip Hopcroft; Elizabeth A. Coker; Patricia Jaaks; Mathew J. Garnett; Beverley Isherwood; Violeta Serra; Barry R. Davies; Simon T. Barry; James T. Lynch; Kosuke Yusa

Affiliations

Kyoto University - Author
Wellcome Sanger Institute - Author

Abstract

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? 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?i and AKTi through mTORC1. However, deletion of PIK3R2 and INPPL1 drove specific PI3K?i resistance through AKT. Conversely deletion of PIK3CA, ERBB2, ERBB3 increased PI3K?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?i in both sensitive and drug resistant TSC1/2 null cells. The combination effect was BAK but not BAX dependent. The Mcl-1i?+?PI3K?/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?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?i/AKTi sensitive and resistant breast tumours.

Keywords
Good health and well-being

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Oncogene due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2022, it was in position 16/171, thus managing to position itself as a Q1 (Primer Cuartil), in the category Genetics & Heredity. Notably, the journal is positioned above the 90th percentile.

From a relative perspective, and based on the normalized impact indicator calculated from the Field Citation Ratio (FCR) of the Dimensions source, it yields a value of: 5.92, which indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: Dimensions May 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-05-23, the following number of citations:

  • Scopus: 17
  • Open Alex: 8
  • OpenCitations: 9
Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-05-23:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 28.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 28 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 1.75.
  • The number of mentions on the social network X (formerly Twitter): 5 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.
Continuing with the social impact of the work, it is important to emphasize that, due to its content, it can be assigned to the area of interest of ODS 3 - Good Health And Well-being, with a probability of 86% according to the mBERT algorithm developed by Aurora University.
Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: Japan.