Endogenous pAKT activity is associated with response to AKT inhibition alone and in combination with immune checkpoint inhibition in murine models of TNBC
Year: 2024
Type: article
Abstract: 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.
Source: Cancer Letters
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,260
Funders: U.S. Department of Veterans Affairs, AstraZeneca, Vanderbilt University, Vanderbilt-Ingram Cancer Center, National Institutes of Health, Vanderbilt Digestive Diseases Research Center, Vanderbilt University Medical Center, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: G1243813451, G1300984159, G1388609297, G2268269956, Leica Bond RX, G283432789, Optimizing Response to Immune Checkpoint Inhibitor Therapy for Breast Cancer: A Role for Inhibitors of the PI3K pathway, G3152736877, G3261201894, G3269002440, G3433274139, G3526814, G359867969, Enhancing triple negative breast cancer response to immune checkpoint inhibitor therapy via targeted therapies, G5853943267, Chemokine Signals in the Premetastatic Niche Inhibit Metastasis, G7520984233, G7709962112, G813343541, G9000312249, Microenvironmental Influences in Cancer, Molecular and Cellular Basis for Digestive Diseases, Cancer Center Support Grant
OpenAlex ID: W4391507913