Molecular changes in the phosphatidylinositide 3-kinase (PI3K) pathway are common in gastric cancer

Thang N Tran1, Kate Brettingham-Moore, Cuong P Duong

  • 1Surgical Oncology Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

Abstract

Insights

Molecular alterations in the phosphatidylinositide 3-kinase (PI3K) pathway are common in gastric cancer. These frequent PI3K pathway changes suggest it is a viable therapeutic target for treating this disease.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • The phosphatidylinositide 3-kinase (PI3K) pathway is crucial in cellular signaling and frequently dysregulated in various cancers.
  • PI3K inhibitors are emerging as promising therapeutic agents for cancer treatment.
  • Understanding PI3K pathway alterations in gastric cancer is essential for targeted therapy development.

Purpose of the Study:

  • To determine the frequency of molecular alterations within the PI3K pathway in human gastric cancer specimens and cell lines.
  • To investigate the prevalence of PIK3CA mutations, copy number gains, and PTEN loss in gastric tumors.
  • To explore potential associations between PI3K pathway alterations and clinical features of gastric cancer.

Main Methods:

  • Screening of 61 gastric cancer specimens and 9 cell lines for PIK3CA mutations using direct sequencing.
  • Assessment of PIK3CA copy number gain via multiplex ligation-dependent probe amplification (MLPA).
  • Evaluation of PTEN protein levels using immunohistochemistry.

Main Results:

  • PI3K pathway alterations were identified in 54% (33/61) of gastric tumors.
  • PIK3CA mutations occurred in 4.9% (3/61) and copy number gains in 13.1% (8/61) of samples.
  • PTEN loss was observed in 39% (24/61) of tumors; no significant associations with clinical features were found.

Conclusions:

  • Frequent alterations in the PI3K pathway underscore its significance in gastric tumorigenesis.
  • The PI3K pathway represents a rational and validated therapeutic target for gastric cancer treatment.

Related Concept Videos

PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
IP3/DAG Signaling Pathway01:11

IP3/DAG Signaling Pathway

Membrane lipids such as phosphatidylinositol (PI) are precursors for several membrane-bound and soluble second messengers. Specific kinases phosphorylate PI and produce phosphorylated inositol phospholipids. One such inositol phospholipids are the  phosphatidylinositol-4,5 bisphosphate [PI(4,5)P2], present in the inner half of the lipid bilayer. Upon ligand binding, GPCR stimulates Gq proteins to turn on phospholipase Cꞵ. Activated phospholipase Cꞵ cleaves PI(4,5)P2 and produces two-second...
Phosphoinositides and PIPs01:42

Phosphoinositides and PIPs

Phosphoinositides are a group of phospholipids containing a glycerol backbone with two fatty acid chains and a phosphate attached to a myoinositol sugar ring. The inositol head group extends into the cytoplasm, where it is modified by adding phosphate groups to form phosphatidylinositol phosphates or PIPs.
Different phosphoinositides are synthesized and recruited on the cytosolic face of the plasma membrane. The localization of specific phosphoinositides concentrated in separate membrane...
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...