Molecular Pathways: Targeting the PI3K Pathway in Cancer—BET Inhibitors to the Rescue

Abstract

The phosphoinositide 3-kinase (PI3K) signaling pathway is a complex and tightly regulated network that is critical for many physiological processes such as cell growth, proliferation, metabolism and survival. Aberrant activation of this pathway can occur through mutation of almost any of its major nodes and has been implicated in a number of human diseases including cancer. The high frequency of mutations in this pathway in multiple types of cancer has led to the development of small molecule inhibitors of PI3K, several of which are currently in clinical trials. However, several feedback mechanisms either within the PI3K pathway or in compensatory pathways can render tumor cells resistant to therapy. Recently, targeting proteins of the bromodomain and extra-terminal (BET) family of epigenetic readers of histone acetylation has been shown to effectively block adaptive signaling response of cancer cells to inhibitors of the PI3K pathway, which at least in some cases can restore sensitivity. BET inhibitors also enforce blockade of the MAPK, JAK/STAT and ER pathways suggesting they may be a rational combinatorial partner for divergent oncogenic signals that are subject to homeostatic regulation. Here, we review the PI3K pathway as a target for cancer therapy and discuss the potential use of BET inhibition to enhance clinical efficacy of PI3K inhibitors.

Overcoming ibrutinib resistance by targeting phosphatidylinositol-3-kinase signaling in diffuse large B-cell lymphoma

“…For example, activation of PI3K-beta isoform was identified in preclinical studies after PI3K-alpha was blocked. [40][41][42] Therefore, targeting multiple PI3K isoforms with dual PI3K-isoform specific inhibitors might eliminate compensatory/feedback responses caused by targeting single PI3K-isoform selective drugs. In support, one study showed tumor regression using a PI3K-alpha/delta dual inhibitor (copanlisib) in CD79B(WT)/MYD88(mut) patient-derived IR ABC-DLBCL cells, underscoring a genetic mechanism of ibrutinib resistance regulated by PI3K isoforms.…”

p110γ deficiency protects against pancreatic carcinogenesis yet predisposes to diet-induced hepatotoxicity

“…While the p110α and β are ubiquitously expressed, p110γ and δ are found predominantly in macrophages and leukocytes, although an increasing number of studies show that p110γ is also expressed to varying degrees in other cell types (11,12), including pancreatic islets (13,14), where its biological function is still not fully appreciated. Class IA PI3Ks can be activated downstream of receptor tyrosine kinases (RTKs), G protein-coupled receptors (GPCRs), and small GTPases (15). All catalytic PI3K isoforms contain an RASbinding domain, although only p110α, δ, and γ isoforms are directly stimulated by RAS (16).…”

Risk stratification for lung adenocarcinoma on EGFR and TP53 mutation status, chemotherapy, and PD‐L1 immunotherapy

“…SDGS also has three genes, MXD4 , BRD2 , and AP2A2 that are known to be associated with TP53 . As described in Results, the association of MXD4 and BRD2 with TP53 is through direct or indirect interaction with the MYC family, which is influenced by TP53 mutation . In addition, both AP2A2 and TP53 enhance the asymmetric segregation of cancer stem cells …”

“…BRD2 is a member of the bromodomains and extra‐terminal domain (BET) family, which interacts with acetylated chromatin and transcription complexes to control transcription, and can bind MYC to drive tumorigenesis in lung cancer . BRD2 interacts with Runx3 to form a complex, and inactivation of Runx3 is an important early event in the development of LUAD …”

“…These studies suggest BRD2 could be a target to battle EGFR resistance to TKIs. Inhibition of BET proteins also increases the clinical efficacy of PI3K inhibitors . Since BRD2 is in a downstream pathway of EGFR signaling, its inhibition could affect EGFR resistance to TKIs.…”