Mutant PIK3CA is a targetable driver alteration in histiocytic neoplasms

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasm driven by MAPK pathway alterations, notably BRAFV600E mutations.
• Activating mutations in other kinases like PIK3CA, ALK, RET, and CSF1R have been observed in histiocytic neoplasms, but PIK3CA's role in hematopoietic cells was unclear.

Purpose of the Study:

• To investigate the role of PIK3CA mutations in driving histiocytic neoplasms.
• To evaluate the efficacy of PI3K inhibition using alpelisib in PIK3CA-mutated LCH.

Main Methods:

• Generated a conditional knockin mouse model expressing PIK3CAH1047R in monocyte/dendritic cell progenitors.
• Treated a patient with multisystemic LCH harboring a PIK3CA mutation using alpelisib.

Main Results:

• The PIK3CAH1047R mouse model demonstrated that these mutations can drive histiocytic neoplasms in vivo.
• Alpelisib treatment resulted in complete clinical and metabolic remission in the patient with PIK3CA-mutated LCH, with a tolerable safety profile.

Conclusions:

• PIK3CA is identified as a targetable, noncanonical driver of LCH.
• These findings emphasize the importance of mutational analysis for personalized treatment strategies in histiocytic neoplasms.