Genomic Determinants of PI3K Pathway Inhibitor Response in Cancer

Abstract

The phosphoinositide 3-kinase (PI3K) pathway is frequently activated in cancer as a result of genetic (e.g., amplifications, mutations, deletions) and epigenetic (e.g., methylation, regulation by non-coding RNAs) aberrations targeting its key components. Several lines of evidence demonstrate that tumors from different anatomical sites depend on the continued activation of this pathway for the maintenance of their malignant phenotype. The PI3K pathway therefore is an attractive candidate for therapeutic intervention, and inhibitors targeting different components of this pathway are in various stages of clinical development. Burgeoning data suggest that the genomic features of a given tumor determine its response to targeted small molecule inhibitors. Importantly, alterations of different components of the PI3K pathway may result in distinct types of dependencies and response to specific therapeutic agents. In this review, we will focus on the genomic determinants of response to PI3K, dual PI3K/mechanistic target of rapamycin (mTOR), mTOR, and AKT inhibitors in cancer identified in preclinical models and clinical trials to date, and the development of molecular tools for the stratification of cancer patients.

Picking the Point of Inhibition: A Comparative Review of PI3K/AKT/mTOR Pathway Inhibitors

“…The phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway is one of the most frequently dysregulated signaling cascades in human malignancies and is implicated in a wide variety of different neoplasms (1). Oncogenic PI3K/AKT/mTOR signaling (summarized in Fig.…”

Proliferation of PTEN‐deficient haematopoietic tumour cells is not affected by isoform‐selective inhibition of p110β PI3‐kinase and requires blockade of all class 1 PI3K activity

“…Previous data in solid tumours has implicated the p110 isoform as playing a key role in mediating proliferative responses in malignancies that lack PTEN [reviewed in Jia et al (2009)]. This has led to the suggestion that p110 selective agents should be tested in such patients and at least one trial is in progress, NCT01458067 (Weigelt & Downward, 2012). Loss and/or mutational inactivation of PTEN is found in T-cell acute lymphoblastic leukaemia (T-ALL), B-cell non-Hodgkin lymphomas and myeloma (COSMIC database, http://www.…”

“…An initial panel of compounds, including an inhibitor of all class 1 PI3Ks (PIK90) and selective inhibitors of p110 (TGX221), p110 (IC87114) and p110 (AS604850) (Foster et al, 2012), was used to investigate the effects of blocking PI3K activity on cell proliferation. Optimal concentrations that fully inhibit the relevant isoform(s) were used based on the literature and previous experiments (Foukas et al, 2010;Weigelt & Downward, 2012). In myeloma cells, proliferation was markedly inhibited by PIK90 but not by TGX221, IC87114, AS604850 or combinations thereof (Fig 1B).…”

“…There is a great deal of interest in targeting PI3Ks for the treatment of cancer and a broad range of compounds are in development (Weigelt & Downward, 2012), including isoform-selective and pan-PI3K inhibitors. p110 selective inhibitors are showing significant activity in chronic lymphocytic leukaemia (Herman & Johnson, 2012).…”

“…p110 and are thought to be ubiquitously expressed, whereas the and isoforms are relatively restricted to the haematopoietic compartment. The PI3K pathway is frequently activated in malignant disease by mechanisms including activating mutations in PIK3CA and deletions/inactivating mutations of the lipid phosphatase PTEN (a negative regulator of PI3K signalling) [reviewed in Weigelt and Downward (2012)]. …”