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Related Concept Videos

MAPK Signaling Cascades01:07

MAPK Signaling Cascades

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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...
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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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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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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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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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Related Experiment Video

Updated: Nov 18, 2025

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
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Mutations in the RAS/MAPK Pathway Drive Replication Repair-Deficient Hypermutated Tumors and Confer Sensitivity to

Brittany B Campbell1,2, Melissa A Galati1,2, Simone C Stone3

  • 1Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.

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This summary is machine-generated.

Replication repair-deficient (RRD) cancers show increased RAS/MAPK pathway mutations. These hypermutant tumors are sensitive to MEK inhibitors, offering new targeted therapy options.

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Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • The RAS/MAPK pathway is a key target in cancer therapy, typically driven by single oncogene mutations.
  • Hypermutant tumors, characterized by numerous somatic mutations, can complicate the identification of actionable genomic alterations.
  • Replication repair-deficient (RRD) cancers are hypermutant and often affect children with genetic predispositions.

Purpose of the Study:

  • To investigate the role of RAS/MAPK pathway mutations in RRD cancers.
  • To determine if RRD hypermutant tumors are sensitive to targeted therapies like MEK inhibition.

Main Methods:

  • Analysis of RAS/MAPK mutation enrichment in RRD cancers.
  • Assessment of RAS/MAPK pathway activation at transcriptional and protein levels in patient-derived RRD tumors.
  • Evaluation of MEK inhibitor efficacy in vitro and in vivo models, and in patient treatment.

Main Results:

  • RRD cancers exhibit significant enrichment of RAS/MAPK pathway mutations (P = 10^-8).
  • These mutations are subclonal, increase in frequency over time, and lead to pathway activation.
  • MEK inhibition demonstrated efficacy in vitro, in vivo, and resulted in durable responses in patients with RRD hypermutant gliomas.

Conclusions:

  • Hypermutant RRD cancers are addicted to the RAS/MAPK pathway, making them susceptible to targeted therapies.
  • Targeting the activated RAS/MAPK pathway offers a promising therapeutic strategy for polyclonal hypermutant cancers.
  • This study highlights the potential of pathway-targeted therapy in RRD hypermutant tumors.