Table 1.

Clinical obstacles to PI3K inhibitor efficacy and proposed solutions

Clinical obstacles	Proposed solutions
Sub-optimal patient selection	•  Selection of patients with tumors harboring activating PIK3CA mutations  •  Identification of PI3K-dependent cancers (i.e., endocrine-resistant ER+ breast cancers with PIK3CA mutations)  •  Exclusion of tumors harboring biomarkers of resistance in PIK3CA-mutant tumors (i.e., KRAS, TP53, or FGFR1)  •  Identification of other genotypes that may benefit from PI3K inhibitors (i.e., PIK3R1 mutations or PIK3CA amplification)
Drug-related toxicity limits target inhibition	•  Focus on isoform-specific inhibitors  •  Development of PIK3CA mutant-selective inhibitors
Feedback upregulation of compensatory mechanisms	•  Use of combinations that limit adaptive response (i.e., with antiestrogens, RTK and PI3Kβ inhibitors, CDK4/6 inhibitors)  •  Optimizing dosing schedules of combinations to ameliorate toxicities
Increase in insulin production upon systemic inhibition of PI3Kα	•  Combinations with SGLT2 inhibitors or ketogenic diet  •  Development of PIK3CA mutant-selective inhibitors