Related Experiment Video

Updated: Jun 23, 2026

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer
06:51

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

PI3K pathway activation mediates resistance to MEK inhibitors in KRAS mutant cancers

Susan Wee1, Zainab Jagani, Kay Xiaoqin Xiang

  • 1Novartis Institutes for BioMedical Research, Cambridge, MA, USA. susan.wee@bms.com

Cancer Research
|April 30, 2009
PubMed

Insights

RAS and PI3K pathway activation impacts cancer cell sensitivity to MEK inhibitors. Targeting both pathways is crucial for effective cancer treatment and tumor stasis in RAS-mutant cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling Pathways

Background:

  • The RAS pathway is frequently deregulated in cancer, signaling through MAPK and PI3K-AKT cascades.
  • Activating mutations in BRAF and PIK3CA, and PTEN loss-of-function, are common in cancer.
  • RAS-mutant cancers show variable sensitivity to MEK inhibitors, unlike BRAF-mutant cancers.

Purpose of the Study:

  • To investigate the influence of PI3K pathway activation on MEK inhibitor sensitivity in RAS-mutant cancers.
  • To elucidate the molecular mechanisms behind heterogeneous responses to MEK inhibition.
  • To provide a rationale for combination therapies targeting MEK and PI3K pathways.

Main Methods:

  • Assessing MEK inhibitor sensitivity in RAS-mutant cancer cells with varying PI3K pathway alterations.
  • Investigating the effects of PIK3CA down-regulation on MEK inhibitor response.
  • Evaluating the impact of dual MEK and PI3K pathway inhibition on downstream effectors and cell death.
  • Testing the efficacy of single versus dual pathway inhibition in preclinical tumor models.

Main Results:

  • PI3K pathway activation, particularly via PIK3CA mutations, reduces sensitivity to MEK inhibitors.
  • PTEN mutations confer complete resistance to MEK inhibition.
  • Down-regulating PIK3CA restores MEK inhibitor sensitivity in KRAS/PIK3CA co-mutant cells.
  • Dual inhibition of MEK and PI3K pathways is necessary for complete mTOR pathway inhibition and cell death induction.
  • Targeting both pathways achieves tumor stasis, whereas single-pathway inhibition causes only partial growth inhibition.

Conclusions:

  • PI3K pathway status is a critical determinant of MEK inhibitor efficacy in RAS-mutant cancers.
  • Combination therapy targeting both MEK and PI3K pathways is essential for overcoming resistance and achieving significant anti-tumor activity.
  • These findings support the clinical investigation of combined MEK and PI3K targeted therapies for RAS-mutant cancers.

More Related Videos

Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies09:29

Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies

Published on: September 30, 2016

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...
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...
MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
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...
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...