PI3K signaling in breast cancer: therapeutic advances versus adaptive resistance
Fabiana Napolitano, Nisha Unni, Carlos L. Arteaga
Fabiana Napolitano, Nisha Unni, Carlos L. Arteaga
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PI3K signaling in breast cancer: therapeutic advances versus adaptive resistance

Abstract

Somatic alterations in the phosphoinositide 3-kinase (PI3K) pathway are frequent oncogenic drivers in cancer and are particularly relevant in estrogen receptor–positive breast cancer, where PI3K signaling integrates hormonal, growth factor, and metabolic inputs. Therapeutic targeting of PI3K has been limited by toxicity, pathway crosstalk, and adaptive resistance. Recent advances in structural and functional characterization of PIK3CA mutations have enabled the development of more selective inhibitors, including PI3K isoform–selective and emerging allosteric PI3Ka mutant–targeted compounds. These approaches aim to improve the therapeutic index while maintaining pathway inhibition. In parallel, combination strategies with endocrine therapy and CDK4/6 inhibitors have demonstrated clinical benefit in selected patient populations. However, responses are often transient owing to compensatory signaling and pathway reactivation. Additional metabolic and transcriptional adaptations further contribute to sustaining tumor cell survival. Overall, PI3K-targeted therapy is evolving along two complementary paths: increased mutant-selective inhibition to improve therapeutic index and broader pathway-level strategies designed to overcome adaptive resistance and achieve more durable responses. Ongoing efforts focus on optimizing combination strategies, enhancing development of predictive biomarkers, and improving therapeutic sequencing to achieve durable responses while minimizing toxicity.

Authors

Fabiana Napolitano, Nisha Unni, Carlos L. Arteaga

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Figure 2

Landscape of PIK3CA mutations and their predicted functional consequences.

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Landscape of PIK3CA mutations and their predicted functional consequence...
(A) Lollipop plot of the PIK3CA gene, illustrating exons, domain organization, and position of point mutations. The GENIE cohort v19.0-public was interrogated for PIK3CA mutation frequency, type, and position in the breast cancer cohort (n = 6,812 specimens/6,044 patients) (5). PIK3CA (p110α) comprises five functional domains: the adaptor-binding domain (ABD, in green), which mediates interaction with the regulatory p85 subunit; the Ras-binding domain (RBD, in red), which binds active RAS proteins and contributes to enzyme activation; the C2 domain (in blue), involved in membrane association and interaction with p85; the helical domain (in yellow), which regulates kinase activity through interactions with the p85 nSH2 domain; and the kinase domain (in purple), which contains the catalytic site responsible for phosphorylation of PIP2. (B) Schematic representation of PI3K activation and oncogenic PI3Kα mutations. In the basal state (left), PI3K is maintained in an inactive conformation through inhibitory intramolecular interactions within the regulatory p85 subunit (N- and C-terminal SH2 domains) and the catalytic p110α subunit. Upon growth factor stimulation, activated RTKs recruit p85 via SH2-phosphotyrosine interactions, thus releasing the nSH2-mediated inhibition of p110α. This allows A-loop exposure and engagement of PIP2 in the membrane, resulting in enzymatic activation and conversion of PIP2 to PIP3. RAS-GTP can further enhance membrane recruitment and activation. Oncogenic mutations promote constitutive PI3K activation through distinct mechanisms. Helical domain mutations (E542K/E545K) disrupt the inhibitory interaction between the p85 nSH2 domain and p110α, enabling PI3K activation even in absence of RTK activation. In contrast, the H1047R mutation enhances membrane interaction and A-loop protrusion, increasing catalytic activity.