Endogenous pAKT activity is associated with response to AKT inhibition alone and in combination with immune checkpoint inhibition in murine models of TNBC.

Autor: Bullock KK; Tennessee Valley Healthcare System, Department of Veteran Affairs, Nashville, TN, USA; Department of Pharmacology, Vanderbilt School of Medicine, Nashville, TN, USA., Shattuck-Brandt R; Tennessee Valley Healthcare System, Department of Veteran Affairs, Nashville, TN, USA; Department of Pharmacology, Vanderbilt School of Medicine, Nashville, TN, USA., Scalise C; Tennessee Valley Healthcare System, Department of Veteran Affairs, Nashville, TN, USA; Department of Pharmacology, Vanderbilt School of Medicine, Nashville, TN, USA., Luo W; Tennessee Valley Healthcare System, Department of Veteran Affairs, Nashville, TN, USA; Department of Pharmacology, Vanderbilt School of Medicine, Nashville, TN, USA., Chen SC; Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA., Saleh N; Tennessee Valley Healthcare System, Department of Veteran Affairs, Nashville, TN, USA; Department of Pharmacology, Vanderbilt School of Medicine, Nashville, TN, USA., Gonzalez-Ericsson PI; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA., Garcia G; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA., Sanders ME; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA., Ayers GD; Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA., Yan C; Tennessee Valley Healthcare System, Department of Veteran Affairs, Nashville, TN, USA; Department of Pharmacology, Vanderbilt School of Medicine, Nashville, TN, USA. Electronic address: chi.yan@vanderbilt.edu., Richmond A; Tennessee Valley Healthcare System, Department of Veteran Affairs, Nashville, TN, USA; Department of Pharmacology, Vanderbilt School of Medicine, Nashville, TN, USA; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address: ann.richmond@vanderbilt.edu.
Jazyk: angličtina
Zdroj: Cancer letters [Cancer Lett] 2024 Apr 01; Vol. 586, pp. 216681. Date of Electronic Publication: 2024 Feb 03.
DOI: 10.1016/j.canlet.2024.216681
Abstrakt: Triple-negative breast cancer (TNBC) is a heterogeneous and challenging-to-treat breast cancer subtype. The clinical introduction of immune checkpoint inhibitors (ICI) for TNBC has had mixed results, and very few patients achieved a durable response. The PI3K/AKT pathway is frequently mutated in breast cancer. Given the important roles of the PI3K pathway in immune and tumor cell signaling, there is an interest in using inhibitors of this pathway to increase the response to ICI. This study sought to determine if AKT inhibition could enhance the response to ICI in murine TNBC models. We further sought to understand underlying mechanisms of response or non-response to AKT inhibition in combination with ICI. Using four murine TNBC-like cell lines and corresponding orthotopic mouse tumor models, we found that hyperactivity of the PI3K pathway, as evidenced by levels of phospho-AKT rather than PI3K pathway mutational status, was associated with response to AKT inhibition alone and in combination with ICI. Additional mutations in other growth regulatory pathways could override the response of PI3K pathway mutant tumors to AKT inhibition. Furthermore, we observed that AKT inhibition enhanced the response to ICI in an already sensitive model. However, AKT inhibition failed to convert ICI-resistant tumors, to responsive tumors. These findings suggest that analysis of both the mutational status and phospho-AKT protein levels may be beneficial in predicting which TNBC tumors will respond to AKT inhibition in combination with ICI.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Published by Elsevier B.V.)
Databáze: MEDLINE
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