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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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Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
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The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
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Updated: May 21, 2025

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Targeting the SHOC2-RAS interaction in RAS-mutant cancers.

Zachary J Hauseman1, Frédéric Stauffer2, Kim S Beyer2

  • 1Novartis BioMedical Research, Cambridge, MA, USA.

Nature
|May 7, 2025
PubMed
Summary
This summary is machine-generated.

Researchers identified SHOC2 as a dependency in RAS(Q61*) cancers, enabling the development of new targeted therapies. Small molecules targeting the SHOC2-RAS interaction inhibit cancer cell growth, offering a promising new avenue for cancer treatment.

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Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
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Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
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Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Activating mutations in rat sarcoma (RAS) genes are common oncogenic drivers in human cancers.
  • While KRAS inhibitors are emerging, effective therapies for NRAS(Q61*) mutants, prevalent in melanoma, are still needed.

Purpose of the Study:

  • To identify dependencies in RAS(Q61*) tumors.
  • To discover and develop novel therapeutic agents targeting the SHOC2-RAS interaction.

Main Methods:

  • Identified SHOC2 as a dependency in RAS(Q61*) tumors.
  • Utilized X-ray co-crystal structure to elucidate the NRAS(Q61R)-SHOC2 interaction.
  • Performed in vitro high-throughput screening to discover small molecules targeting SHOC2.
  • Conducted structure-based optimization to develop a tool compound.

Main Results:

  • SHOC2 was identified as a dependency in a nucleotide-state-dependent and isoform-agnostic manner.
  • A direct interaction between oncogenic NRAS(Q61R) and SHOC2 was confirmed via X-ray crystallography.
  • Small molecules inhibiting the SHOC2-NRAS(Q61*) interaction were discovered.
  • A tool compound demonstrated inhibition of MAPK signaling and proliferation in RAS-mutant cancer models, particularly NRAS(Q61*).

Conclusions:

  • The SHOC2-RAS protein interaction is a druggable target for cancer therapy.
  • This study provides a foundation for developing novel therapies targeting the RAS signaling pathway.
  • Targeting SHOC2 offers a promising strategy for treating NRAS-mutant cancers.