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Related Concept Videos

Targeted Cancer Therapies02:57

Targeted Cancer Therapies

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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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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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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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Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
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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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Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
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Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
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Targeting effector pathways in RAC1P29S-driven malignant melanoma.

Cristina Uribe-Alvarez1, Sandra Lucía Guerrero-Rodríguez2, Jennifer Rhodes1

  • 1Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USA.

Small Gtpases
|February 12, 2020
PubMed
Summary

Targeting Group A PAKs, PI3Kβ, and SRF/MRTF shows promise for treating RAC1-mutant melanoma. These pathways are crucial for melanoma cell growth, offering new therapeutic avenues.

Keywords:
MelanomaPAKPI3KRAC1SRF/MRTFsmall GTPase

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Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Malignant melanoma often harbors mutations in driver genes like BRAF and NRAS.
  • Activating mutations in RAC1 are found in 4-9% of sun-exposed melanomas, impacting cell functions.
  • RAC1 signaling involves key effectors: Group A p21-activated kinases (PAKs), phosphoinositol-3-kinases (PI3Ks), and serum-response factor/myocardin-related transcription factor (SRF/MRTF).

Purpose of the Study:

  • To investigate the roles of PI3Ks and SRF/MRTF in RAC1-driven melanomagenesis.
  • To evaluate the efficacy of inhibiting Group A PAKs, PI3Ks, and SRF/MRTF in melanoma models.

Main Methods:

  • Utilized selective inhibitors: Group A PAK inhibitor (Frax-1036), pan-PI3K (BKM120), PI3Kβ inhibitors (TGX221, GSK2636771), and an SRF/MRTF inhibitor (CCG-203,971).
  • Assessed the impact of these inhibitors on melanoma cell growth in vitro.
  • Evaluated therapeutic effects in a zebrafish embryonic development model in vivo.

Main Results:

  • Group A PAK, PI3Kβ, and pan-PI3K inhibitors effectively impeded growth of RAC1-mutant melanoma cells, but not BRAF-mutant cells.
  • Selective inhibitors for PI3Kα, δ, and γ showed less efficacy.
  • In vivo studies in zebrafish corroborated the in vitro findings, demonstrating therapeutic potential.

Conclusions:

  • Targeting Group A PAKs, PI3Kβ, and SRF/MRTF pathways presents a promising therapeutic strategy for malignant melanoma with RAC1 mutations.
  • These findings offer new insights into RAC1 signaling pathways and potential drug targets in melanoma treatment.