PI3K Signaling Pathway in Cancer Therapeutics

The phosphoinositide 3-kinase (PI3K) signalling cascade occupies a central role in the regulation of cell growth, survival and metabolism, and its dysregulation represents one of the most frequent oncogenic events across human malignancies. Activation of PI3K by receptor tyrosine kinases or G-protein-coupled receptors leads to phosphorylation of phosphatidylinositol-4,5-bisphosphate (PIP2) to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3), which in turn recruits and activates downstream effectors such as AKT and mTOR. Mutations in PIK3CA, loss of the lipid phosphatase PTEN or altered expression of regulatory subunits (for example p85) potentiate the pathway, driving unchecked proliferation, angiogenesis and resistance to apoptosis. Efforts to intercept this axis have yielded a variety of inhibitors, including pan-PI3K, dual PI3K/mTOR and isoform-selective agents. Despite demonstrable antitumour activity, clinical responses have been tempered by on-target toxicities and adaptive resistance, prompting exploration of combination regimens, predictive biomarkers and isoform-biased targeting to enhance therapeutic index and durability of response.

Research from Nature Portfolio

Recent studies have elucidated the impact of oncogenic PIK3CA mutations on the structural regulation and membrane engagement of the PI3K catalytic subunit. Biophysical analyses have revealed how alterations in the adaptor-binding domain and C-terminal region modulate membrane recruitment and catalytic activation, thereby informing the design of mutation-selective inhibitors with improved specificity. Parallel work in tumour genomic profiling has charted the landscape of PIK3CA and PIK3R1 mutations in diverse patient cohorts, uncovering mutually exclusive patterns of alteration, clonal advantages in proliferation and hormone receptor-linked susceptibilities. These insights underpin precision-medicine strategies, matching specific mutational profiles to bespoke PI3K-targeted therapies. A complementary mechanistic investigation into the prototypic inhibitor buparlisib has deconvoluted its dual activity on PI3K and microtubules, guiding the synthesis of derivatives that selectively inhibit PI3K or tubulin dynamics, and offering a blueprint for minimising off-target cytotoxicity while retaining antiproliferative efficacy.

PI3K Signaling Pathway in Cancer Therapeutics publication trend

The graph below shows the total number of articles in pi3k signaling pathway in cancer therapeutics across all publications each year (not limited to Nature Index journals).

Technical terms

Phosphoinositide 3-kinase (PI3K): lipid kinase family that phosphorylates phosphoinositides to generate second messengers involved in cell growth and survival.

AKT: serine/threonine kinase activated by PI3K-generated PIP3, regulating proliferation, metabolism and apoptosis.

mTOR: mechanistic target of rapamycin, a central kinase integrating nutrient and growth signals downstream of PI3K/AKT.

PIK3CA: gene encoding the p110α catalytic subunit of class I PI3K, frequently mutated in a range of cancers.

Isoform-specific inhibitor: small molecule that selectively targets a single PI3K isoform to enhance efficacy and limit off-target toxicity.

References

1. Oncogenic mutations of PIK3CA lead to increased membrane recruitment driven by reorientation of the ABD, p85 and C-terminus. Nature Communications (2023).
2. Targeting PI3K in cancer: mechanisms and advances in clinical trials. Molecular Cancer (2019).
3. Targeting PI3K/Akt signal transduction for cancer therapy. Signal Transduction and Targeted Therapy (2021).
4. The PTEN–PI3K Axis in Cancer. Biomolecules (2019).
5. PI3K Inhibitors in Cancer: Clinical Implications and Adverse Effects. International Journal of Molecular Sciences (2021).
6. Characterization of PIK3CA and PIK3R1 somatic mutations in Chinese breast cancer patients. Nature Communications (2018).
7. The Phosphoinositide 3-Kinase Regulatory Subunit p85α Can Exert Tumor Suppressor Properties through Negative Regulation of Growth Factor Signaling. Cancer Research (2010).
8. Deconvolution of Buparlisib’s mechanism of action defines specific PI3K and tubulin inhibitors for therapeutic intervention. Nature Communications (2017).