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Related Concept Videos

The Ras Gene02:38

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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.
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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.
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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.
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Using RNA-sequencing to Detect Novel Splice Variants Related to Drug Resistance in In Vitro Cancer Models
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Single-cell sensor analyses reveal signaling programs enabling Ras-G12C drug resistance.

Jason Z Zhang1,2,3, Shao-En Ong4, David Baker5,6,7

  • 1Department of Biochemistry, University of Washington, Seattle, WA, USA. jason.zhang0428@gmail.com.

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|August 5, 2024
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Clinical resistance to KRas-G12C inhibitors is a challenge. Single-cell analysis reveals adaptive signaling and metabolic changes in resistant cancer cells, identifying major vault protein as a key mediator.

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Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Clinical resistance to rat sarcoma virus (Ras)-G12C inhibitors poses a significant challenge in cancer therapy.
  • The immediate adaptive effects on Ras signaling at the single-cell level in response to these drugs are not well understood.

Purpose of the Study:

  • To profile the activity and signaling environment of endogenous Ras at the single-cell level in response to Ras-G12C inhibitors.
  • To understand the adaptive signaling and metabolic changes that contribute to drug resistance.

Main Methods:

  • Utilized Ras biosensors for single-cell level profiling of endogenous Ras activity.
  • Analyzed signaling and metabolic adaptations in KRas-G12C cells treated with Ras-G12C inhibitors.

Main Results:

  • Identified a subpopulation of KRas-G12C cells exhibiting adaptive signaling and metabolic changes.
  • Observed distinct roles for wild-type Ras at the Golgi and mutant KRas at the mitochondria in mediating resistance.
  • Discovered major vault protein as a mediator of Ras activation through scaffolding signaling components and metabolite channels.

Conclusions:

  • Single-cell analysis methods can reveal cellular adaptations to cancer therapies, providing insights into drug resistance mechanisms.
  • Understanding these adaptations, including the role of major vault protein, is crucial for overcoming resistance to Ras-G12C inhibitors.