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BCL2L11 Induction Mediates Sensitivity to Src and MEK1/2 Inhibition in Thyroid Cancer

Madison M Rose1, Veronica L Espinoza1, Katelyn J Hoff2

  • 1Division of Endocrinology, Metabolism, and Diabetes, School of Medicine, University of Colorado Anschutz Medical Campus, Mail Stop 7103, Aurora, CO 80045, USA.

Cancers
|January 21, 2023
PubMed

Insights

Targeting Src and MAPK pathways with dasatinib and trametinib shows promise for advanced thyroid cancer. This combination upregulates the BIM protein, enhancing sensitivity and offering a potential therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Advanced thyroid cancers, including papillary and anaplastic types, have poor prognoses due to limited effective therapies.
  • Thyroid cancers frequently harbor MAPK pathway driver mutations (BRAF, RAS, RET) and Src kinase overexpression, presenting therapeutic targets.
  • Previous research indicated synergistic effects of combined Src and MAPK pathway inhibition in thyroid cancer cells.

Purpose of the Study:

  • To identify key mediators of sensitivity and resistance to combined dasatinib and trametinib treatment in advanced thyroid cancer.
  • To explore the role of the pro-apoptotic protein BCL2L11 (BIM) in response to combined Src and MAPK inhibition.
  • To evaluate strategies for overcoming resistance to this combined therapy.

Main Methods:

  • Investigated the molecular mechanisms underlying sensitivity and resistance to dasatinib (Src inhibitor) and trametinib (MEK/MAPK inhibitor) in thyroid cancer cells.
  • Assessed the expression and role of BCL2L11 (BIM) in response to combined treatment.
  • Evaluated the efficacy of targeting BCL-XL with ABT-263 in overcoming treatment resistance.

Main Results:

  • Combined dasatinib and trametinib treatment led to BIM upregulation in sensitive cells, associated with FAK/Src, MEK/ERK, and AKT inhibition.
  • Resistant cells exhibited lack of AKT inhibition and dampened BIM induction.
  • Targeting BCL-XL with ABT-263 successfully sensitized resistant cells by overcoming the lack of BIM induction.

Conclusions:

  • Combined Src and MEK1/2 inhibition is a promising therapeutic strategy for advanced thyroid cancer.
  • BCL2L11 (BIM) induction serves as a potential predictive biomarker for response to this combined therapy.
  • Targeting BCL-XL represents a viable approach to overcome resistance in patients unresponsive to initial combined treatment.
Keywords:
BIMMAPKSrccombinationdasatinibtargeted therapythyroid cancertrametinib

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