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On series |PIK3CA gene mutation and targeted therapy
Dec. 07 2023


  The study of cancer has been extended from single genes to macrogenes, and from single omics to multiple omics. Identifying key points in the complex of signaling pathways and biomolecules is critical for cancer awareness and related drug development. Overactivation of phosphoinositide3-kinases (PI3K) signaling pathway is one of the hallmarks of malignant tumors [1]. Given its key role in cancer, it has been an important target for related research and drug development for more than 20 years.

PI3Ks signaling pathway and PIK3CA gene

  PI3K belongs to the lipid kinase family, which is mainly divided into three types (type I/II/III), among which Class I PI3Ks consists of a dimer composed of a catalytic subunit and a regulatory subunit. Because of the different catalytic subunits, it is divided into four subtypes: PI3Kα/β/γ/δ, the corresponding catalytic subunit p110α/β/γ/δ (the corresponding gene of the catalytic subunit is PIK3CA/B/G/D). In addition, according to different regulatory subunits and functions, ClassⅠPI3Ks can be divided into Class ⅰA (PI3Kα/β/δ) and Class ⅰb (PI3Kγ) (Figure 1) [2,3,4]. The PIK3CA gene encodes the catalytic subunit p110α, which has five domains (Figure 1). PIK3CA mutations are common in breast cancer, endometrial cancer, bladder cancer, colorectal cancer, etc. (Figure 2). The discovery of cancer-specific mutations in PIK3CA in 2004 brought it into the spotlight as a key driver of cancer and a potential drug target [5] (Table 1).

Figure 1. Class Ⅰ PI3Ks signaling pathway

Figure 2. PIK3CA mutations in cancer (source: cBioPortal)


































Research progress of PI3K inhibitors

  PI3K inhibitors can be divided into three categories: pan-PI3K inhibitors, selective inhibitors of PI3K subtypes, and dual inhibitors [6] (Figure 4). Pan-pi3k inhibitors inhibit all four subtypes of Class I PI3Ks, which are associated with a variety of physiological functions, such as glucose metabolism, inflammation, and immunity. Therefore, pan-PI3K inhibitors inevitably increase safety risks, especially the high incidence of metabolically related adverse events, such as hyperglycemia [7]. To reduce toxicity, subunit selective inhibitors were subsequently developed. Studies have reported that p110γ is mainly expressed in white blood cells, and p110δ is highly expressed in hematopoietic cells [8], and related targeted drugs are mostly used for hematoma. Mutations in the p110α catalytic subunit encoded by PIK3CA gene have a high incidence in solid tumors [9]. In addition, dual inhibitors of PI3K/mTOR are also under development, which are effective against all PI3K subtypes as well as mTOR, resulting in inhibition of three key intersections of the PI3K/AKT/mTOR signaling pathway. Currently, the inhibitors approved by the FDA belong to the first two types, among which the breast cancer targeting drug Alpelisib is widely used in the clinic because of its significant efficacy. Alpelisib (Apelis) was approved by the FDA in 2019 for use in combination with the endocrine therapy fulvestrant (fluvestrant) for the treatment of advanced or metastatic breast cancer in hormone receptor (HR) positive, human epidermal growth factor 2 (HER2) negative postmenopausal women and men carrying PIK3CA mutations. Related clinical trials have shown that the progression free survival of patients with breast disease carrying PIK3CA mutations is 11 months VS5.7 months in the treated and placebo groups (Figure 3). In addition, the risk of disease progression or death was significantly reduced by 35%, while the overall response rate (ORR) was more than doubled (36%vs16%) [10].

Figure 3. Kaplan-Meier analysis of progression-free survival

  Alpelisib and other drugs already on the market are undergoing clinical studies in combination or additional indications, and new targeted drugs are also being developed. In China, in 2022, the NMPA conditionally approved the new drug marketing application of Linperlisib from Heng Rui Pharmaceutical for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) who have previously received at least two systemic therapies. CYH33, a PI3Kα-targeting drug for solid tumors such as breast cancer, is also being tested in clinical trials. In the ClinicalTrials database, there are more than 90 clinical studies of PI3K-targeting drugs in the pipeline. The research of PI3K inhibitors is in the ascends. With the continuous understanding of cancer mechanism and target protein configuration, more and more drugs will be developed for clinical application [11].

Figure 4.PI3K inhibitors

Clinical significance of PIK3CA mutation in the treatment of breast cancer

  As a common mutation in cancer, most mutations in PIK3CA are located near the hot spots of E542K, E545K, and H1047. It is associated with drug resistance and poor prognosis in cancer treatment. Kim et al. demonstrated that HER2+ breast cancer patients with PIK3CA mutations treated with palliative HER2-targeted therapy have a lower pathologically complete response rate (pCR) and shorter progression-free survival compared to wild-type. Pooled analyses of several prospective clinical trials using neoadjuvant regiments of chemotherapy plus trastuzumab or lapatinib or a combination of both also showed that the pCR rate was significantly lower in the PIK3CA mutant group than in the wild-type group (16.2%vs.29.6%; p<0.001)[12]. The breast cancer treatment benefited from the significant clinical efficacy of Apeliris, which was included in the NCCN guidelines just over a month after the FDA approved the treatment. At the same time that the FDA approved Alpelisib, it also approved Qiagen's therascreen®PIK3CARGQPCR kit as its companion diagnostic product to detect PIK3CA mutations in tissue and/or liquid biopsies. Alpelisib is recommended for patients who test positive. Guidelines recommend tissue or blood PIK3CA gene testing for HR positive/HER2-negative breast cancer patients considering Alpelisib; For postmenopausal breast cancer patients with PIK3CA gene mutation and HER2-negative, the Fulvestrant+Alpelisib combination is preferred (Figure 5).

Figure 5. Description of PIK3CA mutation detection in the NCCN guidelines

MEDx TMC PIK3CA gene mutation detection kit

  Based on ARMS multiple PCR technology, MEDx TMC designed and developed a human PIK3CA gene mutation detection kit (PCR-fluorescent probe method). On the basis of the 11 mutation sites detected by similar Qiagen products, three sites with high mutation frequency were added (Figure 6), and a total of 14 mutations could be detected. This kit is suitable for tissue samples and plasma samples, high sensitivity, can detect mutations as low as 0.5%, detection speed, 5 to 6 hours to produce results.

Figure 6. Some mutation sites and their locations detected by the Majer Medical Kit


[1] Fruman DA, Chiu H, Hopkins BD, Bagrodia S, Cantley LC, Abraham RT. The PI3K Pathway in Human Disease. Cell. 2017;170(4):605-635. doi:10.1016/j.cell.2017.07.029

[2] Vanhaesebroeck, Bart et al. “PI3K inhibitors are finally coming of age.” Nature reviews. Drug discovery vol. 20,10 (2021): 741-769. doi:10.1038/s41573-021-00209-1

[3] Sirico M, D'Angelo A, Gianni C, Casadei C, Merloni F, De Giorgi U. Current State and Future Challenges for PI3K Inhibitors in Cancer Therapy. Cancers (Basel). 2023;15(3):703. Published 2023 Jan 23. doi:10.3390/cancers15030703

[4] Yu M, Chen J, Xu Z, et al. Development and safety of PI3K inhibitors in cancer. Arch Toxicol. 2023;97(3):635-650. doi:10.1007/s00204-023-03440-4

[5] Samuels Y, Wang Z, Bardelli A, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004;304(5670):554. doi:10.1126/science.1096502

[6] Hillmann P, Fabbro D. PI3K/mTOR Pathway Inhibition: Opportunities in Oncology and Rare Genetic Diseases. Int J Mol Sci. 2019;20(22):5792. Published 2019 Nov 18. doi:10.3390/ijms20225792

[7] De Santis MC, Gulluni F, Campa CC, Martini M, Hirsch E. Targeting PI3K signaling in cancer: Challenges and advances. Biochim Biophys Acta Rev Cancer. 2019;1871(2):361-366. doi:10.1016/j.bbcan.2019.03.003

[8] Thorpe LM, Yuzugullu H, Zhao JJ. PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. Nat Rev Cancer. 2015;15(1):7-24. doi:10.1038/nrc3860

[9] Arafeh R, Samuels Y. PIK3CA in cancer: The past 30 years. Semin Cancer Biol. 2019;59:36-49. doi:10.1016/j.semcancer.2019.02.002

[10] 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. doi:10.1056/NEJMoa1813904

[11] Glaviano A, Foo ASC, Lam HY, et al. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer. Mol Cancer. 2023;22(1):138. Published 2023 Aug 18. doi:10.1186/s12943-023-01827-6

[12] Kim JW, Lim AR, You JY, et al. PIK3CA Mutation is Associated with Poor Response to HER2-Targeted Therapy in Breast Cancer Patients. Cancer Res Treat. 2023;55(2):531-541. doi:10.4143/crt.2022.221)

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