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 1

PI3K signaling and crosstalk with ERα and MAPK pathways.

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PI3K signaling and crosstalk with ERα and MAPK pathways. (A) RTK activat...
(A) RTK activation recruits class IA PI3K (p85α/p110α), promoting conversion of PIP2 to PIP3 at the plasma membrane. PIP3 recruits PDK1 and AKT, enabling AKT phosphorylation by PDK1 (on Thr308) and by mTORC2 (on Ser473). AKT inhibits the TSC1/2 complex, relieving suppression of Rheb and activating mTORC1, which drives mRNA translation, lipid and nucleotide synthesis, and inhibits autophagy through S6K1 signaling. PDK1 can activate SGK1, which can also phosphorylate and inhibit TSC2, thereby sustaining AKT-independent residual mTORC1 activity. Both AKT and SGK1 phosphorylate FOXO3, promoting its cytoplasmic sequestration and functional inactivation. When not phosphorylated, FOXO3 translocates to the nucleus where it induces transcriptional programs that compensate for PI3K inhibition. Additional regulatory inputs from LKB1/AMPK signaling and PTEN-mediated PIP3 dephosphorylation are shown as negative modulators of the pathway. (B) Crosstalk between PI3K signaling, MAPK, and ERα happens at multiple nodes. PI3K can activate MAPK via interaction with KRAS. Activated AKT can phosphorylate ERα, activating ligand-independent transcription of ER-target genes. Ligand activated and/or phosphorylated ERα can bind RTKs via adaptor proteins (e.g., Src) and favor phosphorylation of RTKs at tyrosines in their C-terminus. These residues provide docking sites for p85 and activation of p110α, the catalytic subunit of PI3K.