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Related Concept Videos

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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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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Skin Cancer01:30

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Skin cancer is a type of cancer that occurs when there is an abnormal growth of skin cells, usually triggered by damage to the DNA within the skin cells. It is primarily caused by exposure to ultraviolet (UV) radiation from the sun or artificial sources like tanning beds. Skin cancer is the most common type of cancer worldwide, and its incidence continues to rise.
Basal Cell Carcinoma (BCC): BCC is the most common type of skin cancer, accounting for about 80% of cases. It typically develops in...
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Related Experiment Video

Updated: Mar 16, 2026

Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells
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How Melanoma Resists PD-1 Blockade

    Cancer Discovery
    |August 4, 2016
    PubMed
    Summary

    Melanoma cells can resist pembrolizumab by disabling interferon-gamma signaling through JAK1/JAK2 mutations or by impairing antigen presentation via B2M mutations. These findings reveal key resistance mechanisms to PD-1 blockade therapy.

    Area of Science:

    • Oncology
    • Immunology
    • Genetics

    Background:

    • Melanoma is a significant skin cancer with increasing incidence.
    • PD-1 blockade immunotherapy, such as with pembrolizumab, has revolutionized melanoma treatment.
    • Understanding mechanisms of therapeutic resistance is crucial for improving patient outcomes.

    Purpose of the Study:

    • To elucidate the molecular mechanisms underlying melanoma resistance to PD-1 blockade therapy with pembrolizumab.

    Main Methods:

    • Analysis of melanoma cell lines and patient samples.
    • Genetic sequencing to identify mutations in key signaling pathways.
    • Functional assays to assess interferon-gamma signaling and antigen presentation.

    Main Results:

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    • Identified loss-of-function mutations in Janus kinase 1 (JAK1) or Janus kinase 2 (JAK2) that abrogate interferon-gamma signaling.
    • Discovered a truncating mutation in beta-2-microglobulin (B2M) leading to defective antigen presentation.
    • Demonstrated that these genetic alterations confer resistance to pembrolizumab treatment.

    Conclusions:

    • Melanoma resistance to pembrolizumab can arise from defects in interferon-gamma signaling or antigen presentation pathways.
    • JAK1/JAK2 and B2M mutations represent critical genetic drivers of resistance.
    • Targeting these pathways may offer strategies to overcome immunotherapy resistance in melanoma.