PIK3CD

Overview

PIK3CD encodes the catalytic p110-delta subunit of PI3K, a class I PI3K isoform typically expressed in leukocytes. Rare activating mutations in PIK3CD have been identified in solid tumors as mechanisms of acquired resistance to targeted therapies, with at least one variant demonstrated to enhance AKT signaling.

Alterations observed in the corpus

  • PIK3CD S367L variant was identified in an escape lesion from a patient with HER2-positive metastatic esophagogastric cancer (EGC) progressing on pembrolizumab + trastuzumab + chemotherapy; this variant demonstrated increased AKT phosphorylation in functional assays, suggesting it is an activating resistance mutation PMID:37406106.
  • Predicted damaging mutation identified in RMS2107 rhabdomyosarcoma sample; member of the PI3K signaling pathway PMID:24436047
  • Private PI3K-pathway event of unknown significance in paired primary/metastasis CRC cohort; detected in spatially separate tumor regions indicating subclonality PMID:25164765
  • PIK3CD is a recurrent driver in DLBCL but CRISPR knockout did NOT impair growth, suggesting it may act in early pathogenesis or via non-targetable functions in established DLBCL PMID:28985567

Cancer types (linked)

  • Esophagogastric cancer (EGC / STAD / ESCA) — PIK3CD S367L identified as an acquired resistance mechanism in HER2-positive disease treated with HER2 + PD-1 blockade PMID:37406106.

Co-occurrence and mutual exclusivity

  • PIK3CD S367L co-occurred with other resistance-associated alterations in the escape lesion (loss of HER2 expression, PI3K pathway activation) in the context of combined HER2/PD-1 blockade PMID:37406106.

Therapeutic relevance

  • PIK3CD S367L-driven PI3K pathway activation represents a potential resistance mechanism to HER2-directed therapy; PI3K or AKT inhibitors may overcome this resistance in HER2-positive EGC PMID:37406106.

Open questions

  • The frequency of PIK3CD mutations as a resistance mechanism in HER2-positive solid tumors beyond EGC is unknown; the S367L variant may be a rare but functionally relevant event warranting systematic assessment by ctDNA monitoring.

Sources

This page was processed by crosslinker on 2026-05-09. - PMID:24436047

This page was processed by crosslinker on 2026-05-09. - PMID:25164765

This page was processed by wiki-cli on 2026-05-11. - PMID:28985567

This page was processed by wiki-cli on 2026-05-15.