October 23, 2024

Importance of PI3K-AKT pathway-based biomarkers in breast cancer

Significance of PI3K/AKT deregulation

PI3K/AKT (Phosphatidylinositol-3-kinase/protein kinase B) signaling is one of the most important and frequently overactivated intracellular pathways, which can be considered a master regulator for cancer.1 Affecting downstream target proteins, the pathway contributes to the carcinogenesis, proliferation, invasion, and metastasis of tumor cells.2 Multidrug resistance and the development of several different types of cancers, e.g., breast, colorectal, glioblastoma, gastric, lung, kidney, uterine, bladder, urethral, endometrial and others are at least partly caused by PI3K/AKT deregulation.3-5

PI3K

PI3K is an oncogenic group of plasma membrane-associated lipid kinases which are generally activated by extracellular signals, such as growth factors, cytokines, and hormones.1 Mutations that occur in PI3K and in tumor suppressor genes, e.g., in the tensin homolog (PTEN), which inhibits progression of the pathway by reverting PI3K-generated Phosphatidylinositol (3,4,5)-trisphosphate (PIP3) back to Phosphatidylinositol 4,5-bisphosphate (PIP2), are the major mutations responsible for the dysregulation of the PI3K/AKT pathway in human tumors.6,7

AKT

AKT is an intracellular kinase that plays an important role in cell survival and apoptosis. A variety of signaling proteins, such as AKT, can bind to the lipid products of PI3K and localize to the cell membrane to activate cell growth and regulate basic processes like cell survival, proliferation, differentiation, angiogenesis, and metabolism.8

Pathways

The main downstream target of PI3K/AKT is the serine/threonine kinase, mTOR. The PI3K/AKT/mTOR pathway is not only involved in the regulation of the proliferation and apoptosis of cancer cells but it also promotes normal and tumor angiogenesis.9 Deregulation of the PI3K/AKT pathway can occur from oncogenic mutations in the PIK3CA gene. The PIK3CA gene, which encodes the catalytic subunit of PI3K, is mutated at a high frequency in tumor tissues.10

The AKT1 somatic cell mutation was first found in breast cancer, but has since been identified in lung, colorectal, bladder, endometrium, prostate, and other cancers and it is present in 4-8% of breast cancer patients.11,12 The E17K hotspot is the most characteristic mutation of the AKT1 gene which can activate the PI3K/AKT/mTOR pathway and lead to tumorgenesis.13 However, the relationship is not without caveats as some studies have shown an antitumor effect and a positive impact on the survival of breast cancer patients with an E17K mutation.13 More studies need to be done to properly assess the impact of this mutation.

Detection of mutations in P13K/AKT pathway

Sysmex Inostics’ BC-SEQ using Plasma-Safe-SeqS (PSS) technology is capable of detecting mutations targeting PIK3CA and AKT1. With robust detection, as low as 0.03% mutant allele frequency for input of 20,000 genomic equivalents, PSS ensures acquisition of reliable molecular information for real-time therapy selection as well as monitoring of tumor response.14 PSS can play an important role in improving patient care when these clinically-relevant mutations are detected early with high sensitivity and specificity.

Implications of using highly sensitive technology

PI3K/AKT/mTOR pathway has been shown to be dysregulated in almost all human cancers. Using highly sensitive technology to detect mutations in the PI3K/AKT/mTOR pathway will:

  • allow maximum identification of biomarker-positive patients eligible for therapy
  • accurately monitoring disease response and clonal dynamics for informed adaptation of therapeutic strategies15
  • detect minimal residual disease (MRD) and be used during recurrence surveillance16

Highly sensitive NGS liquid-biopsy technology will help develop therapeutics that enhance every phase of a patient’s journey and extend lives. Further studies should be conducted to investigate the effect of PIK3CA mutations on clinical outcomes in different histologic types, different molecular subtypes of breast cancer, and different exons of PIK3CA.

References:

  1. https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-019-0954-x
  2.  https://www.mdpi.com/2072-6694/13/16/3949/htm
  3. Samuels, Y. et al. (2010) Oncogenic mutations of PIK3CA in human cancers. Curr Top Microbiol Immunol.347:21-41.
  4. Alqahtani, A. et al. (2019) PIK3CA Gene Mutations in Solid Malignancies: Association with Clinicopathological Parameters and Prognosis. Cancers. 12:93. doi: 10.3390/cancers12010093.
  5. Murph, M.M. et al. (2008) Individualized molecular medicine: Linking functional proteomics to select therapeutics targeting the PI3K pathway for specific patients. Adv Exp Med Biol.622:183-95. (deregulation)
  6. Vanhaesebroeck, B. et al. (2010) The emerging mechanisms of isoform-specific PI3K signalling. Nat Rev Mol Cell Biol.11:329-41.
  7. Song, M.S. et al. (2012) The functions and regulation of the PTEN tumour suppressor. Nature reviews. Mol Cell Biol. 13:283-96.
  8. https://www.ahajournals.org/doi/10.1161/01.res.0000022200.71892.9f
  9. Zhou, Y. et al. (2017) Effect of microRNA-135 on cell proliferation, migration, invasion, apoptosis and tumor angiogenesis through the IGF-1/PI3K/Akt signaling pathway in non-small cell lung cancer. Cell Physiol Biochem.42:1431-46.
  10. Saal, L.H. et al. (2005) PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res.65:2554-59. doi: 10.1158/0008-5472-CAN-04-3913.
  11. Huo, X. et al. (2019) Clinical and expression significance of AKT1 by co-expression network analysis in endometrial cancer. Front Oncol. 9:1147.
  12. Wang, J. et al. (2019) MAT1 facilitates the lung metastasis of osteosarcoma through upregulation of AKT1 expression. Life Sci.234:116771.
  13. Salhia, B. et al. (2012) Differential effects of AKT1(p.E17K) expression on human mammary luminal epithelial and myoepithelial cells. Hum Mutat.33:1216-27.
  14. https://sysmex-inostics.com/products/plasma-safe-seqs/
  15. Dawson, S.J. et al. (2013) Analysis of Circulating Tumor DNA to Monitor Metastatic Breast Cancer. N Engl J Med. 368:1199-209. doi:10.1056/NEJMoa1213261.
  16. Rodriguez, B.J. et al. (2019) Detection of TP53 and PIK3CA Mutations in Circulating Tumor DNA Using Next-Generation Sequencing in the Screening Process for Early Breast Cancer Diagnosis. J Clin Med. 8(8):1188. doi: 10.3390/jcm8081183.