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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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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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Organisms are capable of detecting and fixing nucleotide mismatches that occur during DNA replication. This sophisticated process requires identifying the new strand and replacing the erroneous bases with correct nucleotides. Mismatch repair is coordinated by many proteins in both prokaryotes and eukaryotes.
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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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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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Dependence of NPPS creates a targetable vulnerability in RAS-mutant cancers.

Rui-Xue Xia1,2, Pei-Chen Zou2, Jun-Ting Xie2

  • 1Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.

Acta Pharmacologica Sinica
|November 6, 2024
PubMed
Summary

Researchers identified nucleotide pyrophosphatase (NPPS) as a key vulnerability in RAS-mutant cancers. Inhibiting NPPS or its interaction with hexokinase 1 (HK1) effectively suppressed tumor growth, offering a new therapeutic strategy for these challenging cancers.

Keywords:
HK1NPPSRAS-mutant cancersglycolysis

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Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • RAS mutations are frequent drivers of cancer, but targeted therapies remain limited for many RAS variants beyond KRAS G12C.
  • Existing KRAS G12C inhibitors have advanced treatment paradigms, yet a significant unmet need persists for other RAS-mutated cancers.
  • Identifying novel, broadly applicable targets within the RAS pathway is crucial for developing effective pan-RAS mutant cancer therapies.

Purpose of the Study:

  • To explore pivotal regulatory molecules enabling broad inhibition of diverse RAS mutants.
  • To investigate the role of nucleotide pyrophosphatase (NPPS) in RAS-mutant cancer growth and survival.
  • To evaluate NPPS inhibition as a potential therapeutic strategy for RAS-mutant cancers.

Main Methods:

  • Comparative analysis of NPPS expression in RAS-mutant versus RAS-wildtype cell lines.
  • Transcriptomics and metabolomics to elucidate NPPS-dependent metabolic pathways.
  • In vitro and in vivo studies using NPPS and hexokinase 1 (HK1) inhibitors (Enpp-1-IN-1, 2-deoxyglucose) and genetic interference.

Main Results:

  • RAS-mutant cancer cells exhibit an upregulation and dependence on NPPS for growth and survival.
  • NPPS promotes hyperglycolysis in RAS-mutant cells by enhancing its interaction with HK1, the rate-limiting enzyme in glycolysis.
  • Inhibition of the NPPS-HK1 axis significantly suppressed RAS-mutant cancer progression both in vitro and in vivo.

Conclusions:

  • NPPS is a critical vulnerability and druggable target for a broad spectrum of RAS-mutant cancers.
  • The NPPS-HK1 axis represents a novel mechanism driving hyperglycolysis in RAS-mutant cells.
  • Targeting the NPPS-HK1 axis offers a promising new therapeutic avenue for treating diverse RAS-mutant malignancies.