Related Experiment Video

Updated: May 11, 2026

Exploring the Pharmacological Action and Molecular Mechanism of Salidroside in Inhibiting MCF-7 Cell Proliferation and Migration
11:13

Exploring the Pharmacological Action and Molecular Mechanism of Salidroside in Inhibiting MCF-7 Cell Proliferation and Migration

Published on: June 9, 2023

RSK3/4 mediate resistance to PI3K pathway inhibitors in breast cancer

Violeta Serra1, Pieter J A Eichhorn, Celina García-García

  • 1Experimental Therapeutics, Vall d'Hebron Institute of Oncology, Barcelona, Spain.

The Journal of Clinical Investigation
|May 3, 2013
PubMed

Insights

Resistance to PI3K inhibitors in cancer can be overcome by targeting ribosomal S6 kinases (RSK3 and RSK4). Combined PI3K and RSK inhibition shows promise for treating breast cancer with elevated RSK activity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • The phosphoinositide 3-kinase (PI3K) signaling pathway is crucial for cell regulation and frequently dysregulated in cancer.
  • PI3K inhibitors are under clinical investigation for cancer treatment, showing early efficacy in breast cancer.
  • Acquired or de novo resistance to PI3K inhibitors can limit therapeutic effectiveness.

Purpose of the Study:

  • To systematically identify mechanisms of resistance to PI3K inhibitors.
  • To uncover genes that promote survival during PI3K/mammalian target of rapamycin (PI3K/mTOR) pathway blockade.
  • To evaluate therapeutic strategies combining PI3K and RSK inhibition.

Main Methods:

  • Functional genomics screen to identify resistance genes.
  • In vitro and in vivo studies using breast cancer cell lines and patient-derived xenografts.
  • Assessment of proliferation, apoptosis, and protein translation.
  • Evaluation of MEK or RSK inhibitors in combination with PI3K inhibitors.

Main Results:

  • Overexpression of ribosomal S6 kinases RPS6KA2 (RSK3) and RPS6KA6 (RSK4) confers resistance to PI3K inhibition.
  • RSK3 and RSK4 promote proliferation by attenuating apoptosis and upregulating protein translation.
  • Combined MEK/RSK and PI3K inhibition overcomes resistance in preclinical models.
  • Elevated RSK activity is associated with resistance to PI3K pathway blockade.

Conclusions:

  • RSK3 and RSK4 are key mediators of resistance to PI3K inhibitors.
  • Targeting RSK in combination with PI3K inhibitors is a promising strategy for breast cancer treatment.
  • This approach may benefit patients with activated RSK signaling.

More Related Videos

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

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...
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...
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...
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...
The Ras Gene02:38

The Ras Gene

The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a superfamily...
Receptor Tyrosine Kinases01:26

Receptor Tyrosine Kinases

Receptor tyrosine kinases or RTKs are membrane-bound receptors that phosphorylate specific tyrosine on protein substrates. RTKs regulate cellular growth, differentiation, survival, and migration. They contain an extracellular ligand binding domain, a transmembrane domain, and a cytosolic tail with intrinsic kinase activity. Several extracellular signaling molecules activate RTKs in one or more ways and relay the signal downstream. Ligands such as platelet-derived growth factor (PDGF) or...