Related Experiment Video

Updated: May 4, 2026

Author Spotlight: Exploring Salidroside's Molecular Mechanisms in Breast Cancer Treatment
11:13

Author Spotlight: Exploring Salidroside's Molecular Mechanisms in Breast Cancer Treatment

Published on: June 9, 2023

2.3K

Acquired PIK3CA amplification causes resistance to selective phosphoinositide 3-kinase inhibitors in breast cancer

L-Y Huw1, C O'Brien1, A Pandita2

  • 1Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA, USA.

Oncogenesis
|December 25, 2013
PubMed

Insights

Acquired resistance to PI3K/mTOR inhibitors in breast cancer can occur through PIK3CA gene amplification. This novel mechanism drives resistance by upregulating PI3K signaling, but can be overcome by targeting the amplified gene.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Targeted therapies, including PI3K/mTOR inhibitors, show promise in clinical trials for various cancers.
  • Acquired resistance can limit the efficacy of targeted therapies, necessitating the study of resistance mechanisms.

Purpose of the Study:

  • To investigate a novel mechanism of acquired resistance to PI3K inhibitors in PIK3CA-mutant, HER2-positive breast cancer.
  • To model acquired resistance in preclinical settings and identify actionable targets.

Main Methods:

  • Utilized a HER2-positive, PIK3CA mutant breast cancer cell line (KPL-4) for preclinical modeling.
  • Employed small interfering RNA (siRNA) to knockdown amplified PIK3CA mutant alleles.
  • Assessed PI3K signaling pathway activation and cellular sensitivity to PI3K inhibition.

Main Results:

  • Identified high-level amplification of the mutant PIK3CA allele as a novel mechanism of acquired resistance.
  • Demonstrated that PIK3CA amplification leads to marked upregulation of PI3K signaling, restoring proliferative capacity in resistant cells.
  • Showed that siRNA-mediated knockdown of amplified PIK3CA restored pathway signaling and sensitivity to PI3K inhibition.

Conclusions:

  • PIK3CA gene amplification represents a previously unreported mechanism of acquired resistance to PI3K inhibitors in breast cancer.
  • Evaluating PI3K copy number variation in patient biopsies at disease progression may reveal this resistance mechanism.
  • These findings suggest potential strategies for overcoming acquired resistance to PI3K-targeted therapies.

More Related Videos

Phospholipid Mediator Induced Transformation in Three-Dimensional Cultures08:02

Phospholipid Mediator Induced Transformation in Three-Dimensional Cultures

Published on: July 27, 2022

2.0K
Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer06:51

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer

Published on: July 21, 2018

19.0K

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...
5.1K
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...
3.6K
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...
4.7K
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
4.8K
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...
7.7K
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...
10.2K