A protein network map of head and neck cancer reveals PIK3CA mutant drug sensitivity

Abstract

Mapping protein interactions driving cancer Cancer is a genetic disease, and much cancer research is focused on identifying carcinogenic mutations and determining how they relate to disease progression. Three papers demonstrate how mutations are processed through networks of protein interactions to promote cancer (see the Perspective by Cheng and Jackson). Swaney et al . focus on head and neck cancer and identify cancer-enriched interactions, demonstrating how point mutant–dependent interactions of PIK3CA, a kinase frequently mutated in human cancers, are predictive of drug response. Kim et al . focus on breast cancer and identify two proteins functionally connected to the tumor-suppressor gene BRCA1 and two proteins that regulate PIK3CA. Zheng et al . developed a statistical model that identifies protein networks that are under mutation pressure across different cancer types, including a complex bringing together PIK3CA with actomyosin proteins. These papers provide a resource that will be helpful in interpreting cancer genomic data. —VV

Oncogenic mutations ofPIK3CAlead to increased membrane recruitment driven by reorientation of the ABD, p85 and C-terminus

“…The removal of the nSH2 partially destabilises the iSH2-C2 and ABD-kinase interfaces, but in the wild type complex the equilibrium is mainly towards a closed p85-ABD engaged complex (black arrows). The pYXXM binding surface of the nSH2 exposed in helical mutants leads to greatly enhanced recruitment to RTKs and their adaptors 55 . Oncogenic mutations that occur at the ABD or iSH2 interfaces in p110 (red equilibrium arrows between Fig 6B -6C) shifts the equilibrium towards the disengaged state, leading to increased affinity for membranes.…”

Contemporary Molecular Analyses of Malignant Tumors for Precision Treatment and the Implication in Oral Squamous Cell Carcinoma

“…So far there is no biomarker which can achieve clinical validity and clinical utility, except PD-L1 testing, in oral cancers. However, instead of analyzing a single gene or single or multiple markers, which was the first paradigm shift in precision medicine in NSCLC, using NGS or even multi-omics data, which has become a common tool to analyze broad genetic and molecular alterations, to correlate with treatment outcomes might be a new paradigm shift for precision medicine in oral cancers [7,[64][65][66][67][68].…”

From systems to structure — using genetic data to model protein structures

“…Such networks have proved highly informative, enabling functional annotations of proteins and conveying information on the architectures of entire biological systems 1 , 2 . Protein–protein interaction (PPI) networks describe which proteins interact 3 – 5 (Fig. 1a ).…”