alpelisib

Overview

PI3Kα-selective small-molecule inhibitor targeting PIK3CA-mutant tumors.

Evidence in the corpus

  • One histiocytosis patient with a PIK3CA mutation had a durable response to alpelisib, while two ovarian GCT PIK3CA-mutant patients had no durable response — suggesting lineage-specific conditioning of PI3Kα inhibitor efficacy PMID:36862133.
  • In the UCLA sarcoma PDTO biobank (sarcoma_ucla_2024), a metastatic undifferentiated spindle cell sarcoma (SARC0117) carrying a PIK3CA hotspot mutation (reported as H1074L, corresponding to canonical H1047L) was a top responder to alpelisib and showed broad sensitivity across the PI3K/mTOR class (apitolisib, copanlisib, BGT226, vistusertib). A second specimen (SARC0134, MPNST) carried the same PIK3CA mutation in the primary tumor but did not respond to alpelisib; follow-up sequencing confirmed loss of the PIK3CA mutation in the metastatic lesion. A third specimen (SARC0069_2, osteosarcoma, no PIK3CA mutation) was the top alpelisib responder overall — illustrating biomarker-negative responders. PMID:39305899

Resistance mechanisms

  • Lineage context (ovarian GCT vs histiocytosis) appears to modulate response to PIK3CA-directed therapy PMID:36862133.
  • Loss of the PIK3CA mutation between primary and metastatic tumor (SARC0134, MPNST) abolishes ex vivo alpelisib sensitivity, demonstrating that inter-lesion genomic heterogeneity can undermine biomarker-directed PI3K inhibitor use. PMID:39305899

Cancer types (linked)

  • LCH, ECD, OGCT
  • SARCNOS (undifferentiated spindle cell sarcoma), MPNST, OS — sarcoma subtypes with alpelisib sensitivity data in UCLA PDTO screen.

Sources

  • PMID:36862133
  • PMID:39305899 — Al Shihabi et al. (Cell Stem Cell 2024). UCLA sarcoma PDTO biobank; PIK3CA-dependent and PIK3CA-independent alpelisib sensitivity; inter-lesion heterogeneity as resistance mechanism.

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