Requirement for interaction of PI3-kinase p110α with RAS in lung tumor maintenance
Esther Castellano1, Clare Sheridan, May Zaw Thin
1Signal Transduction Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
Cancer Cell
|November 16, 2013
Summary
RAS proteins activate PI3-kinases. Inhibiting RAS interaction with p110α in established KRAS-driven lung tumors halts growth and causes regression, offering a potential therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- RAS proteins are key regulators of cellular signaling pathways, including the PI3K/AKT pathway.
- Mutations in RAS genes are common in human cancers, driving tumor initiation and progression.
- The role of RAS-PI3K interaction in maintaining established RAS-driven tumors remains incompletely understood.
Purpose of the Study:
- To investigate the necessity of RAS interaction with the p110α subunit of PI3K for the maintenance of established KRAS-driven lung tumors.
- To evaluate the therapeutic potential of disrupting RAS-p110α interaction in established lung cancer models.
Main Methods:
- Utilized an inducible mouse model with mutant KRAS-driven lung tumors.
- Employing genetic manipulation to specifically disrupt the RAS binding domain of p110α in established tumors.
- Assessed tumor stasis and regression following targeted disruption of RAS-p110α interaction.
- Investigated the effects of combining RAS-p110α interaction inhibition with MEK inhibitors.
- Compared outcomes with complete p110α expression or activity ablation.
Main Results:
- Disrupting the interaction between RAS and p110α in established tumors led to long-term tumor stasis and partial regression.
- This effect was demonstrated to be tumor cell-autonomous.
- Combination therapy with MEK inhibition significantly enhanced the anti-tumor effects.
- Complete ablation of p110α expression or activity yielded similar results but with increased toxicity.
Conclusions:
- RAS interaction with p110α is crucial for the maintenance of established KRAS-driven lung tumors.
- Targeting the RAS-p110α interaction presents a promising therapeutic strategy for lung cancer.
- Combination strategies, such as inhibiting RAS-p110α interaction alongside MEK inhibition, may offer improved efficacy and reduced toxicity.
More Related Videos
10:21Author Spotlight: Exploring the Role of Inflammation in the Co-occurrence of Primary Sjogren's Syndrome and Lung Adenocarcinoma
Published on: September 20, 2024
917
07:49Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
Published on: July 17, 2019
5.7K
Related Concept Videos
02:38The Ras Gene
5.7K
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...
Ras is a...
5.7K
01:22PI3K/mTOR/AKT Signaling Pathway
5.2K
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...
5.2K
01:24Small GTPases - Ras and Rho
4.4K
Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:
Three regulatory proteins control their activity:
4.4K
01:20The JAK-STAT Signaling Pathway
10.2K
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
03:03mTOR Signaling and Cancer Progression
3.6K
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 mTOR pathway or the...
3.6K
01:19Interactions Between Signaling Pathways
4.7K
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...
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