A Pan-Cancer Proteogenomic Atlas of PI3K/AKT/mTOR Pathway Alterations

Abstract

Summary Molecular alterations involving PI3K/AKT/mTOR pathway (including mutation, copy number, protein, or RNA) were examined across 11219 human cancers representing 32 major types. Within specific mutated genes, frequency, mutation hotspot residues, in silico predictions, and functional assays were all informative in distinguishing the subset of genetic variants more likely to have functional relevance. Multiple oncogenic pathways including PI3K/AKT/mTOR converged on similar sets of downstream transcriptional targets. In addition to mutation, structural variations and partial copy losses involving PTEN and STK11 showed evidence for having functional relevance. A substantial fraction of cancers showed high mTOR pathway activity without an associated canonical genetic or genomic alteration, including cancers harboring IDH1 or VHL mutations, suggesting multiple mechanisms for pathway activation.

A Pan-Cancer Compendium of Genes Deregulated by Somatic Genomic Rearrangement across More Than 1,400 Cases

“…Previously, pathway-level alterations—according to somatic mutation, CNA, or epigenetic silencing—were surveyed across TCGA, pathways including p53-related (e.g., TP53, RB1 ), the mammalian target of rapamy-cin (mTOR), receptor tyrosine kinase (RTK) signaling, chromatin modification, SWI/SNF complex, Wnt/β-catenin, and MYC (Chen et al, 2017, 2018; Zhang et al, 2017). When considering oncogene- or tumor suppressor-associated genes represented by the above pathways, a high overlap was observed between tumor suppressor genes and genes with decreased expression associated with SV breakpoints (Figure 4A, p < 1E–9, one-sided Fisher’s exact test).…”

Long Non-Coding RNA XLOC_006753 Promotes the Development of Multidrug Resistance in Gastric Cancer Cells Through the PI3K/AKT/mTOR Signaling Pathway

“…To our knowledge, the phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of the rapamycin (PI3K/AKT/mTOR) signaling pathway is one of the main growth regulatory pathways in both normal and cancer cells [33]. The PI3K/AKT/mTOR pathway regulates cell proliferation, differentiation, cellular metabolism, and cytoskeletal reorganization leading to apoptosis and cancer cell survival.…”

Opportunities and Resistance to Signal-Targeted Therapies in Pancreatic Cancer: What Can we Learn from Proteomic Studies?

“…Recent integrated omics approaches on all cancers points out that the search of genetic or genomic alterations is not sufficient to predict which patients will benefit from targeted therapies [26] [69]. In contrast, proteomics appears better in predicting sensitivity to a targeted therapy (PI3K inhibitors) [26], suggesting that proteomic approaches could be a worthwhile strategy to investigate and to better understand the resistance to treatment of pancreatic cancer patients, so as to predict which therapy will be more efficient ( Figure 2). Recent pioneering data which need to be complemented by wider studies argue for the effort to develop such challenging strategies in pancreatic cancer.…”