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Alpelisib: a novel PI3K inhibitor for the treatment of breast cancer
- 1 Shanghai United International School Jiaoke Campus, Shanghai, China, 201400
- 2 China Pharmaceutical University 639 LongMian road, NanJing, China, 210000
- 3 Shunde Wende School Hong Kong Division, Foshan, Guangdong, China, 528000
* Author to whom correspondence should be addressed.
Abstract
Breast cancer is a common malignancy that causes people to die easily, especially for women. HR-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancers occur in more than 70% of patients, who have a driver mutant kinase catalytic subunit alpha (PIK3CA) in the phosphatidylinositol 4, 5-diphosphate 3-kinase gene, resulting in impaired phosphatidylinositol 3-kinase (PI3K) and in 40% of cases, loss of cell growth. However, drug resistance remains a problem in the early stages of endocrine therapy in these patients. And a promising new approach to overcome resistance to autologous treatment in breast cancer is the inhibition of PI3K. Alpelisib is a selection PI3K inhibitor for HR-positive, HER2-negative, PIK3CA patients - with mutant breast cancer that has advanced on autologous treatment. FDA approved alpelisib in 2019 which was produced by Novartis Pharmaceuticals Corporation. It is recommended to take this drug with fulvestrant which is also an estrogen receptor antago-nist that slows the growth of breast cancer. Although alpelisib is an effective drug for the treatment of breast cancer, some adverse reactions may happen, such as stomatitis, nausea, diarrhe, dermatitis, and so on. Sometimes it also causes skin reactions, such as SIS, TEN, EM. Thus, when these serious adverse reactions happen, dosage should be reduced. As a result, some recommendations are provided for patients, and they must follow the instructions in or-der to live a more pleasant life. In this article, the working mechanism, structure, characteris-tics, clinical studies of alpelisib were reviewed and its comparison with other drugs was also provided for reference.
Keywords
Alpelisib, Clinical, Breast cancer
[1]. Ayele, W., Führer, A., Braun, G., Formazin, F., Wienke, A., & Taylor, L. et al. (2022). Breast cancer morbidity and mortality in rural Ethiopia: data from 788 verbal autopsies. BMC Women's Health, 22(1).
[2]. CDC. (2019). CDC - Breast Cancer Statistics. Centers for Disease Control and Prevention.
[3]. Ma CX, Ellis MJ. The Cancer Genome Atlas: clinical applications for breast cancer. Oncology (Williston Park). 2013 Dec;27(12):1263-9, 1274-9.
[4]. Mollon, L., Aguilar, A., et.al. (2018). A systematic literature review of the prevalence of PIK3CA mutations and mutation hotspots in HR+/HER2-metastatic breast cancer. Cancer Research, 78(13 suppl). 10.1158/1538-7445.https://www.cdc.gov/cancer/breast/statistics/index.htm
[5]. Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer. 2009 Aug;9(8):550-62.
[6]. Paplomata E, O'Regan R. The PI3K/AKT/mTOR pathway in breast cancer: targets, trials and biomarkers. Ther Adv Med Oncol. 2014 Jul;6(4):154-66.
[7]. Foster JG, Blunt MD, et al. Inhibition of PI3K signaling spurs new therapeutic opportunities in inflammatory/autoimmune diseases and hematological malignancies. Pharmacol Rev. 2012 Oct;64(4):1027-54.
[8]. Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet. 2006;7(8):606–619.
[9]. Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. Oncogene. 2008;27(41):5497–5510.
[10]. Fruman DA, Meyers RE, Cantley LC. Phosphoinositide kinases. Annu Rev Biochem. 1998; 67: 481–507.
[11]. Yu J, Wjasow C, Backer JM. Regulation of the p85/p110 alpha phosphatidylinositol 3ʹ-kinase. Distinct roles for the N-terminal and C-terminal SH2 domains. J Biol Chem. 1998;273(46):30199–30203.
[12]. Franke TF, Kaplan DR et.al. Direct regulation of the Akt proto-oncogene product by phosphati-dylinositol-3,4-bisphosphate. Science. 1997;275(5300):665–668.
[13]. Klippel A, Kavanaugh WM, et.al. A specific product of phosphatidylinositol 3-kinase directly activates the protein kinase Akt through its pleckstrin homology domain. Mol Cell Biol. 1997;17(1):338–344.
[14]. Mora A, Komander D, van Aalten DMF, Alessi DR. PDK1, the master regulator of AGC ki-nase signal transduction. Semin Cell Dev Biol. 2004;15(2):161–170.
[15]. Sarbassov DD, Guertin DA, et.al. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005;307(5712):1098–1101.
[16]. Wang L, Lawrence JC Jr, et.al. Mammalian target of rapamycin complex 1 (mTORC1) activity is associated with phosphorylation of raptor by mTOR. J Biol Chem. 2009;284(22):14693–14697.
[17]. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149(2):274–293.
[18]. Maehama T, Dixon JE. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid sec-ond messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem. 1998;273(22):13375–13378.
[19]. Mui E，Ambrini G，et al． The phosphoinositide 3-kinase α selective inhibitor BYL719 en-hances the effect of the protein kinase C in- hibitor AEB071 in
[20]. GNAQ/GNA11-mutant uveal melanoma cells． Mol Cancer Ther，2014，13(5): 1044-1053
[21]. PI3K/Akt/mTOR pathway as a therapeutic target for colorectal cancer: a review of preclinical and clinical evidence［J］. Curr Drug Target, 2019, 20（12）:1217-1226.
[22]. Samels Y，Ericon K. Oncogenic PI3K and its role in cancer．Curr Opin Oncol，2006，18(1): 77-82．
[23]. Sarbsov DD, Gutin DA, et.al. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005;307(5712):1098–1101.
[24]. Chang DY, Ma WL, Lu YS. Role of Alpelisib in the PIK3CA-Mutated Breast Cancer: Patient Selection and Clinical Perspectives. Ther Clin Risk Manag. 2021 Mar 5; 17: 193-207.
[25]. Highlights of Prescribing Information Pneumonitis: Severe Cases of ... https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212526s000lbl.pdf.
[26]. “Fulvestrant: Uses, Dosage, Side Effects, Warnings.” Drugs.com, https://www.drugs.com/fulvestrant.html.
[27]. Narayan, P. et al. FDA Approval Summary: Alpelisib plus fulvestrant for patients with HRposi-tive, HER2-negative, PIK3CA-mutated, advanced or metastatic breast cancer. Clin Cancer Res (2020).
[28]. André F, Ciruelos E, Rubovszky G, et al. Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2019;380(20):1929-1940.
[29]. André F, Ciruelos EM, Juric D, et al. Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast can-cer: final overall survival results from SOLAR-1. Ann Oncol. 2021;32(2):208-217.
[30]. Juric D, Ciruelos EM, Rubovszky G et al. Alpelisib (ALP) + fulvestrant (FUL) for advanced breast cancer (ABC): Phase 3 SOLAR-1 trial results. Presented at: San Antonio Breast Cancer Symposium; December 4–8, 2018; San Antonio, TX.
[31]. Rugo HS, Lerebours F, Ciruelos E, et al. Alpelisib plus fulvestrant in PIK3CA-mutated, hor-mone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): one cohort of a phase 2, multicentre, open-label, non-comparative study. The Lancet Oncology. 2021;22(4):489-498.
[32]. Rugo HS, Lerebours F, Ciruelos E et al. Alpelisib + fulvestrant in patients with PIK3CAmutated hormone receptor-positive (HR+), human epidermal growth factor recep-tor-2-negative (HER2-) advanced breast cancer (ABC) previously treated with cyclin-dependent kinase 4/6 inhibitor (CDKi) + aromatase inhibitor (AI): BYLieve study results. Presented at: 56th Annual Meeting of the American Society of Clinical Oncology; May 29–31, 2020; Virtual.
[33]. Turner S, Chia S, Kanakamedala H, Hsu WC, Park J, Chandiwana D, Ridolfi A, Yu CL, Zarate JP, Rugo HS. Effectiveness of Alpelisib + Fulvestrant Compared with Real-World Standard Treatment Among Patients with HR+, HER2-, PIK3CA-Mutated Breast Cancer. Oncolo-gist. 2021 Jul;26(7):e1133-e1142.
Cite this article
Shao,Y.;Yao,Y.;Zhang,M. (2023). Alpelisib: a novel PI3K inhibitor for the treatment of breast cancer. Theoretical and Natural Science,3,475-481.
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