Concurrent PIK3CA mutant drives cachexia through inflammatory signaling in EGFR mutant lung cancer

Abstract

PIK3CA mutation is frequently concurrent with known oncogenic drivers such as EGFR mutation in lung cancer, raising an interesting question about its real function. Cachexia is a systemic disease involving complex interaction between primary tumors and distant organs, significantly contributing to cancer-related mortality. Through integrative study of genetically engineered mouse models (GEMMs) and clinical data, we find concurrent PIK3CA mutant preferentially drives cachexia in EGFR-mutant lung cancer, promoting malignant progression instead of cancer initiation. PIK3CA mutant-mediated cachexia could be overcome by osimertinib (Osi) treatment in Osi-sensitive GEMM. In contrast, chemotherapy, routinely used in clinic for those relapsed from Osi therapy, fails to ameliorate cachexia in Osi-resistant GEMM despite notable tumor suppression. PIK3CA mutant-driven cachexia is mediated through NF-{kappa}B activation and could be dampened by combined aspirin treatment. This work uncovers the biological function of PIK3CA mutant and mechanism behinds its clinical impacts, and proposes a potentially effective strategy for clinical management.