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Updated: Sep 18, 2025
A Melanoma Patient-Derived Xenograft Model
Published on: May 20, 2019
Capacity for compensatory cyclin D2 response confers trametinib resistance in canine mucosal melanoma
Bih-Rong Wei1, Vincenzo Verdi1, Shuling Zhang1
1Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
Background/Objective:
Mucosal melanoma (MM) is a poorly responsive, rare and aggressive subtype with paucity of targetable recurrent driver mutations, although Ras/MAPK and PI3K/AKT/mTOR signaling pathway activations are common. Eventual tumor evasion of targeted therapy continues to limit treatment success. Adequate models are necessary to address therapeutic resistance. The relatively greater incidence of naturally occurring MM in dogs, as well as its comparable clinical and pathological characteristics to human MM, represents a promising opportunity for predictive patient modeling. Resistance-promoting crosstalk between Ras/MAPK and PI3K/AKT/mTOR signaling under trametinib inhibition of MEK was studied in a canine MM model. Emphasis was placed on the suppressive effect of trametinib on cell cycle entry and its potential role in drug resistance.
Methods:
D-type cyclins were investigated using five MM cell lines exhibiting differential sensitivities to trametinib. Drug-treated cells were analyzed for signaling pathway activation, proliferation, survival, cell death, and cell cycle in the context of D-type cyclin expression. Cyclin D2 expression was manipulated using siRNA knock down or inducible recombinant overexpression.
Results:
With diminished cyclin D1 under trametinib treatment, relatively trametinib-resistant MM cells exhibited capacity to upregulate cyclin D2, which promoted proliferation, whereas sensitive cells did not similarly respond. Inhibition of the compensatory cyclin D2 response restored sensitivity to resistant cells. Induced cyclin D2 overexpression promoted survival to otherwise trametinib-sensitive MM cells that did not exhibit capacity to upregulate endogenous cyclin D2. PI3K/AKT/mTOR signaling upregulation under trametinib was suppressed by mTORC1/2 inhibition, which similarly diminished cyclin D2 response.
Conclusion:
The compensatory switch from preferential reliance on cyclin D1 to D2 appears to play a role in MM resistance to MEK inhibition.
Insights
Mucosal melanoma cells can resist MEK inhibitors like trametinib by switching from cyclin D1 to cyclin D2, promoting proliferation. Restoring cyclin D2 levels re-sensitizes resistant cells to trametinib treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Mucosal melanoma (MM) is an aggressive cancer with limited treatment options due to resistance.
- Activating mutations in Ras/MAPK and PI3K/AKT/mTOR pathways are common in MM.
- Canine MM models offer a valuable platform for studying therapeutic resistance in human MM.
Purpose of the Study:
- Investigate the role of D-type cyclins in mediating resistance to MEK inhibition in MM.
- Elucidate the compensatory signaling mechanisms that promote therapeutic evasion.
- Identify potential strategies to overcome drug resistance in MM.
Main Methods:
- Utilized five MM cell lines with varying sensitivities to trametinib.
- Analyzed signaling pathways, proliferation, survival, and cell cycle progression.
- Manipulated cyclin D1 and D2 expression using siRNA and recombinant overexpression.
Main Results:
- Resistant MM cells upregulated cyclin D2 in response to trametinib, promoting proliferation.
- Inhibiting the compensatory cyclin D2 upregulation restored trametinib sensitivity.
- Overexpressing cyclin D2 enhanced survival in otherwise sensitive MM cells.
Conclusions:
- A compensatory switch from cyclin D1 to cyclin D2 drives MM resistance to MEK inhibitors.
- Targeting cyclin D2 or related pathways may overcome trametinib resistance.
- Understanding these resistance mechanisms is crucial for developing effective MM therapies.
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