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Related Concept Videos

The Ras Gene02:38

The Ras Gene

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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.
Ras is a...
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Treatment Resistant Cancers02:56

Treatment Resistant Cancers

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Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
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Small GTPases - Ras and Rho01:24

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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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mTOR Signaling and Cancer Progression03:03

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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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Abnormal Proliferation02:23

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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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Cancer-Critical Genes I: Proto-oncogenes01:33

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Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
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Genetic Drivers of Sensitivity or Resistance to RAS(ON) Multi-Selective Inhibitors in NRAS-Mutated Melanoma.

Mona Foth, Wontak Kim, Kayla T O'Toole

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    |December 25, 2025
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    New inhibitors targeting RAS signaling show promise for NRAS-mutated melanoma. However, resistance can emerge, highlighting the need for combination therapies to improve treatment outcomes for these patients.

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    Area of Science:

    • Oncology
    • Melanoma Research
    • Molecular Targeted Therapy

    Background:

    • Advanced melanoma often presents with BRAF or NRAS mutations, influencing treatment strategies.
    • While BRAF-mutated melanoma has effective second-line therapies post-immunotherapy failure, NRAS-mutated melanoma lacks targeted options.
    • Immunotherapy is a common first-line treatment for advanced melanoma.

    Purpose of the Study:

    • To evaluate the efficacy of RAS(ON) multi-selective inhibitors, specifically RMC-7977 and daraxonrasib, in NRAS-mutated melanoma.
    • To investigate mechanisms of resistance to RAS-targeted monotherapy.
    • To explore the potential of daraxonrasib as a treatment for NRAS-mutated melanoma.

    Main Methods:

    • Preclinical studies using NRAS-mutated melanoma cell lines and animal models.
    • Assessment of anti-proliferative and anti-tumor activity of RAS inhibitors.
    • Analysis of clinical case studies of patients treated with daraxonrasib.

    Main Results:

    • RMC-7977 and daraxonrasib demonstrated potent anti-proliferative and anti-tumor activity in preclinical NRAS-mutated melanoma models.
    • Resistance to RMC-7977 monotherapy was observed in preclinical models due to mutations in Ppia or Map2k1.
    • Clinical data showed anti-tumor activity in one patient treated with daraxonrasib, but progressive disease in another with co-occurring NRAS and MAP2K1 mutations.

    Conclusions:

    • Daraxonrasib shows potential for treating NRAS-mutated melanoma.
    • Mutations in Ppia (CYPA) and Map2k1 (MEK1) are candidate mechanisms for resistance to RAS-targeted monotherapy.
    • Combination therapies are needed to overcome resistance and improve outcomes for NRAS-mutated melanoma patients.