ANALYSIS OF THE EFFECTIVENESS OF DUAL PI3K/mTOR INHIBITORS IN INHIBITION OF PI3K/AKT/mTOR SIGNALING PATHWAY IN BREAST CANCER
Abstract
Breast cancer is a malignancy originating from breast cells, ducts, and tissues that can occur due to genetic mutations due to DNA damage in normal cells. The PI3K/Akt/mTOR pathway is an intracellular pathway that plays an important role in regulating basic cell functions such as cell growth, movement, survival, metabolism, and angiogenesis. Some examples of PI3K/mTOR pathway inhibitor drugs on the market and often used are dactolisib, samotolisib, voxtalisib, and so on. These drugs are more effective than single-pathway inhibitors. This article was prepared using the literature review method. The data used in this article were obtained from the PubMed and Google Scholar using the keywords breast cancer, PI3K/Akt/mTOR inhibitor, and PI3K/AKT/mTOR signaling pathway. Several studies suggest that the PI3K-AKT-mTOR pathway is critical in mediating the proliferation and migration of breast cancer cells. Because of the importance of the PI3K-AKT-mTOR pathway in the pathogenesis of breast cancer, it is often used as a target for breast cancer therapy. PI3K/mTOR dual ATP competitive inhibitors can directly act on the main target proteins of PI3K and mTOR, thereby more efficiently inhibiting the PI3K/AKT/mTOR signaling pathway and effectively preventing other factors that can activate the PI3K pathway, and reducing the resistance and side effects produced by single inhibitors.
Keywords: breast cancer, dual inhibitor, PI3K-AKT-mTOR
References
1. Margan, M.M., Jitariu, A.A., Cimpean, A.M., Nica, C., and Raica, M., 2016. Molecular Portrait of the Normal Human Breast Tissue and Its Influence on Breast Carcinogenesis. J. Breast Cancer, 19: 99–111. DOI: 10.4048/jbc.2016.19.2.99.
2. Łukasiewicz, Ł., Czeczelewski, M., Forma, A., Baj, J., Sitarz, R., and Stanisławek, A., 2021. Breast Cancer—Epidemiology, Risk Factors, Classification, Prognostic Markers, and Current Treatment Strategies— An Updated Review. MDPI, 1–30. .
3. Gautama, W., 2022. Breast Cancer in Indonesia in 2022: 30 Years of Marching in Place. Indones. J. Cancer, 16: 1. DOI: 10.33371/ijoc.v16i1.920.
4. Azmi, A.N., Kurniawan, B., Siswandi, A., and Detty, A.U., 2020. Hubungan Faktor Keturunan Dengan Kanker Payudara DI RSUD Abdoel Moeloek. J. Ilm. Kesehat. Sandi Husada, 12: 702–707. DOI: 10.35816/jiskh.v12i2.373.
5. Globocan., 2022. WHO Indonesia. Indonesia.
6. Paplomata, E., and O’regan, R., 2014. The PI3K/AKT/mTOR pathway in breast cancer: Targets, trials and biomarkers. Ther. Adv. Med. Oncol., 6: 154–166. DOI: 10.1177/1758834014530023.
7. Luo, L., Sun, X., Yang, Y., Xia, L., Wang, S., Fu, Y., Zhu, Y., Xu, S., and Zhu, W., 2023. A Novel Dual PI3K/mTOR Inhibitor, XIN-10, for the Treatment of Cancer. 10.3390/ijms241914821DOI: 10.3390/ijms241914821.
8. Li, Q., Li, Z., Luo, T., and Shi, H., 2022. Targeting the PI3K/AKT/mTOR and RAF/MEK/ERK pathways for cancer therapy. 10.1186/s43556-022-00110-2DOI: 10.1186/s43556-022-00110-2.
9. Mezni, E., Vicier, C., Guerin, M., Sabatier, R., Bertucci, F., and Gonçalves, A., 2020. New therapeutics in HER2-positive advanced breast cancer: Towards a change in clinical practices?pi. Cancers (Basel)., 12: 1–26. DOI: 10.3390/cancers12061573.
10. Park, J.Y., Kang, S.E., Ahn, K.S., Um, J.Y., Yang, W.M., Yun, M., and Lee, S.G., 2020. Inhibition of the PI3K-AKT-mTOR pathway suppresses the adipocyte-mediated proliferation and migration of breast cancer cells. J. Cancer, 11: 2552–2559. DOI: 10.7150/jca.37975.
11. Sun, Y.S., Zhao, Z., Yang, Z.N., Xu, F., Lu, H.J., Zhu, Z.Y., Shi, W., Jiang, J., Yao, P.P., and Zhu, H.P., 2017. Risk factors and preventions of breast cancer. Int. J. Biol. Sci., 13: 1387–1397. DOI: 10.7150/ijbs.21635.
12. Hanahan, D., 2022. Hallmarks of Cancer: New Dimensions. Cancer Discov., 12: 31–46. DOI: 10.1158/2159-8290.CD-21-1059.
13. Lestari, P., and Wulansari., 2018. Pentingnya Pemeriksaan Payudara Sendiri ( SADARI ) Sebagai Upaya Deteksi Dini Kanker Payudara. Indones. J. Community Empower., 1161: 55–58. .
14. Centers for Disease Control and Prevention., 2023. What Is Breast Cancer Screening ? Breast Cancer Screening Tests Where Can I Go to Get Screened ? Breast Self-Awareness. .
15. Martínez-Saéz, O., Chic, N., Pascual, T., Adamo, B., Vidal, M., González-Farré, B., Sanfeliu, E., Schettini, F., Conte, B., Brasó-Maristany, F., Rodríguez, A., Martínez, D., Galván, P., Rodríguez, A.B., Martinez, A., Munõz, M., and Prat, A., 2020. Frequency and spectrum of PIK3CA somatic mutations in breast cancer. Breast Cancer Res., 22: 1–9. DOI: 10.1186/s13058-020-01284-9.
16. Peng, Y., Wang, Y., Zhou, C., Mei, W., and Zeng, C., 2022. PI3K/Akt/mTOR Pathway and Its Role in Cancer Therapeutics: Are We Making Headway? Front. Oncol., 12: 1–17. DOI: 10.3389/fonc.2022.819128.
17. Xu, F., Na, L., Li, Y., and Chen, L., 2020. Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours. 10.1186/s13578-020-00416-0DOI: 10.1186/s13578-020-00416-0.
18. Vanhaesebroeck, B., Perry, M.W.D., Brown, J.R., André, F., and Okkenhaug, K., 2021. PI3K inhibitors are finally coming of age. Nat. Rev. Drug Discov., 20: 741–769. DOI: 10.1038/s41573-021-00209-1.
19. Castel, P., Toska, E., Engelman, J.A., and Scaltriti, M., 2021. The present and future of PI3K inhibitors for cancer therapy. Nat. cancer, 2: 587–597. DOI: 10.1038/s43018-021-00218-4.
20. Porta, C., Paglino, C., and Mosca, A., 2014. Targeting PI3K/Akt/mTOR signaling in cancer. Front. Oncol., 4 APR: 1–11. DOI: 10.3389/fonc.2014.00064.
21. Hu, X., Xia, M., Wang, J., Yu, H., Chai, J., Zhang, Z., Sun, Y., Su, J., and Sun, L., 2020. Dual PI3K/mTOR inhibitor PKI-402 suppresses the growth of ovarian cancer cells by degradation of Mcl-1 through autophagy. Biomed. Pharmacother., 129: 110397. DOI: 10.1016/j.biopha.2020.110397.
22. Tarantelli, C., Lupia, A., Stathis, A., and Bertoni, F., 2020. Is there a role for dual PI3K/mTOR inhibitors for patients affected with lymphoma? Int. J. Mol. Sci., 21: 1–22. DOI: 10.3390/ijms21031060.
23. Zhang, Y., Yan, H., Xu, Z., Yang, B., Luo, P., and He, Q., 2019. Molecular basis for class side effects associated with PI3K/AKT/mTOR pathway inhibitors. Expert Opin. Drug Metab. Toxicol., 15: 767–774. DOI: 10.1080/17425255.2019.1663169.
24. Wu, X., Xu, Y., Liang, Q., Yang, X., Huang, J., Wang, J., Zhang, H., and Shi, J., 2022. Recent Advances in Dual PI3K/mTOR Inhibitors for Tumour Treatment. Front. Pharmacol., 13: 1–17. DOI: 10.3389/fphar.2022.875372.
25. Murase, Y., Hosoya, K., Sato, T., Kim, S., and Okumura, M., 2022. Antitumor activity of the dual PI3K/mTOR inhibitor gedatolisib and the involvement of ABCB1 in gedatolisib resistance in canine tumor cells. Oncol. Rep., 47: 1–10. DOI: 10.3892/or.2022.8272.
2. Łukasiewicz, Ł., Czeczelewski, M., Forma, A., Baj, J., Sitarz, R., and Stanisławek, A., 2021. Breast Cancer—Epidemiology, Risk Factors, Classification, Prognostic Markers, and Current Treatment Strategies— An Updated Review. MDPI, 1–30. .
3. Gautama, W., 2022. Breast Cancer in Indonesia in 2022: 30 Years of Marching in Place. Indones. J. Cancer, 16: 1. DOI: 10.33371/ijoc.v16i1.920.
4. Azmi, A.N., Kurniawan, B., Siswandi, A., and Detty, A.U., 2020. Hubungan Faktor Keturunan Dengan Kanker Payudara DI RSUD Abdoel Moeloek. J. Ilm. Kesehat. Sandi Husada, 12: 702–707. DOI: 10.35816/jiskh.v12i2.373.
5. Globocan., 2022. WHO Indonesia. Indonesia.
6. Paplomata, E., and O’regan, R., 2014. The PI3K/AKT/mTOR pathway in breast cancer: Targets, trials and biomarkers. Ther. Adv. Med. Oncol., 6: 154–166. DOI: 10.1177/1758834014530023.
7. Luo, L., Sun, X., Yang, Y., Xia, L., Wang, S., Fu, Y., Zhu, Y., Xu, S., and Zhu, W., 2023. A Novel Dual PI3K/mTOR Inhibitor, XIN-10, for the Treatment of Cancer. 10.3390/ijms241914821DOI: 10.3390/ijms241914821.
8. Li, Q., Li, Z., Luo, T., and Shi, H., 2022. Targeting the PI3K/AKT/mTOR and RAF/MEK/ERK pathways for cancer therapy. 10.1186/s43556-022-00110-2DOI: 10.1186/s43556-022-00110-2.
9. Mezni, E., Vicier, C., Guerin, M., Sabatier, R., Bertucci, F., and Gonçalves, A., 2020. New therapeutics in HER2-positive advanced breast cancer: Towards a change in clinical practices?pi. Cancers (Basel)., 12: 1–26. DOI: 10.3390/cancers12061573.
10. Park, J.Y., Kang, S.E., Ahn, K.S., Um, J.Y., Yang, W.M., Yun, M., and Lee, S.G., 2020. Inhibition of the PI3K-AKT-mTOR pathway suppresses the adipocyte-mediated proliferation and migration of breast cancer cells. J. Cancer, 11: 2552–2559. DOI: 10.7150/jca.37975.
11. Sun, Y.S., Zhao, Z., Yang, Z.N., Xu, F., Lu, H.J., Zhu, Z.Y., Shi, W., Jiang, J., Yao, P.P., and Zhu, H.P., 2017. Risk factors and preventions of breast cancer. Int. J. Biol. Sci., 13: 1387–1397. DOI: 10.7150/ijbs.21635.
12. Hanahan, D., 2022. Hallmarks of Cancer: New Dimensions. Cancer Discov., 12: 31–46. DOI: 10.1158/2159-8290.CD-21-1059.
13. Lestari, P., and Wulansari., 2018. Pentingnya Pemeriksaan Payudara Sendiri ( SADARI ) Sebagai Upaya Deteksi Dini Kanker Payudara. Indones. J. Community Empower., 1161: 55–58. .
14. Centers for Disease Control and Prevention., 2023. What Is Breast Cancer Screening ? Breast Cancer Screening Tests Where Can I Go to Get Screened ? Breast Self-Awareness. .
15. Martínez-Saéz, O., Chic, N., Pascual, T., Adamo, B., Vidal, M., González-Farré, B., Sanfeliu, E., Schettini, F., Conte, B., Brasó-Maristany, F., Rodríguez, A., Martínez, D., Galván, P., Rodríguez, A.B., Martinez, A., Munõz, M., and Prat, A., 2020. Frequency and spectrum of PIK3CA somatic mutations in breast cancer. Breast Cancer Res., 22: 1–9. DOI: 10.1186/s13058-020-01284-9.
16. Peng, Y., Wang, Y., Zhou, C., Mei, W., and Zeng, C., 2022. PI3K/Akt/mTOR Pathway and Its Role in Cancer Therapeutics: Are We Making Headway? Front. Oncol., 12: 1–17. DOI: 10.3389/fonc.2022.819128.
17. Xu, F., Na, L., Li, Y., and Chen, L., 2020. Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours. 10.1186/s13578-020-00416-0DOI: 10.1186/s13578-020-00416-0.
18. Vanhaesebroeck, B., Perry, M.W.D., Brown, J.R., André, F., and Okkenhaug, K., 2021. PI3K inhibitors are finally coming of age. Nat. Rev. Drug Discov., 20: 741–769. DOI: 10.1038/s41573-021-00209-1.
19. Castel, P., Toska, E., Engelman, J.A., and Scaltriti, M., 2021. The present and future of PI3K inhibitors for cancer therapy. Nat. cancer, 2: 587–597. DOI: 10.1038/s43018-021-00218-4.
20. Porta, C., Paglino, C., and Mosca, A., 2014. Targeting PI3K/Akt/mTOR signaling in cancer. Front. Oncol., 4 APR: 1–11. DOI: 10.3389/fonc.2014.00064.
21. Hu, X., Xia, M., Wang, J., Yu, H., Chai, J., Zhang, Z., Sun, Y., Su, J., and Sun, L., 2020. Dual PI3K/mTOR inhibitor PKI-402 suppresses the growth of ovarian cancer cells by degradation of Mcl-1 through autophagy. Biomed. Pharmacother., 129: 110397. DOI: 10.1016/j.biopha.2020.110397.
22. Tarantelli, C., Lupia, A., Stathis, A., and Bertoni, F., 2020. Is there a role for dual PI3K/mTOR inhibitors for patients affected with lymphoma? Int. J. Mol. Sci., 21: 1–22. DOI: 10.3390/ijms21031060.
23. Zhang, Y., Yan, H., Xu, Z., Yang, B., Luo, P., and He, Q., 2019. Molecular basis for class side effects associated with PI3K/AKT/mTOR pathway inhibitors. Expert Opin. Drug Metab. Toxicol., 15: 767–774. DOI: 10.1080/17425255.2019.1663169.
24. Wu, X., Xu, Y., Liang, Q., Yang, X., Huang, J., Wang, J., Zhang, H., and Shi, J., 2022. Recent Advances in Dual PI3K/mTOR Inhibitors for Tumour Treatment. Front. Pharmacol., 13: 1–17. DOI: 10.3389/fphar.2022.875372.
25. Murase, Y., Hosoya, K., Sato, T., Kim, S., and Okumura, M., 2022. Antitumor activity of the dual PI3K/mTOR inhibitor gedatolisib and the involvement of ABCB1 in gedatolisib resistance in canine tumor cells. Oncol. Rep., 47: 1–10. DOI: 10.3892/or.2022.8272.
Published
2025-12-31
How to Cite
SUSANTO, Andi et al.
ANALYSIS OF THE EFFECTIVENESS OF DUAL PI3K/mTOR INHIBITORS IN INHIBITION OF PI3K/AKT/mTOR SIGNALING PATHWAY IN BREAST CANCER.
Medika Kartika : Jurnal Kedokteran dan Kesehatan, [S.l.], v. 8, n. 4, p. 434-445, dec. 2025.
ISSN 2655-6537.
Available at: <http://medikakartika.unjani.ac.id/medikakartika/index.php/mk/article/view/972>. Date accessed: 07 jan. 2026.
Section
Articles
