MEK and MCL-1 sequential inhibition synergize to enhance rhabdomyosarcoma treatment
Clara Alcon1, Fernando Martín1,2, Estela Prada3,4
1Institute for Bioengineering of Catalonia (IBEC), Barcelona Institute of Science and Technology (BIST), 08028, Barcelona, Spain.
Abstract:
Targeted agents have emerged as promising molecules for cancer treatment, but most of them fail to achieve complete tumor regression or attain durable remissions due to tumor adaptations. We used dynamic BH3 profiling to identify targeted agents effectiveness and anti-apoptotic adaptations upon targeted treatment in rhabdomyosarcoma. We focused on studying the use of BH3 mimetics to specifically inhibit pro-survival BCL-2 family proteins, overwhelm resistance to therapy and prevent relapse. We observed that the MEK1/2 inhibitor trametinib rapidly depleted the pro-apoptotic protein NOXA, thus increasing MCL-1 availability. Indeed, we found that the MCL-1 inhibitor S63845 synergistically enhanced trametinib cytotoxicity in rhabdomyosarcoma cells in vitro and in vivo. In conclusion, our findings indicate that the combination of a BH3 mimetic targeting MCL-1 with trametinib improves efficiency on rhabdomyosarcoma by blocking tumor adaptation to treatment.
Insights
This study reveals that combining trametinib with an MCL-1 inhibitor overcomes resistance in rhabdomyosarcoma. This targeted therapy approach blocks tumor adaptation, improving treatment effectiveness and preventing relapse.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Targeted cancer therapies show promise but often face tumor adaptation, limiting efficacy.
- Rhabdomyosarcoma treatment requires strategies to overcome therapeutic resistance and prevent relapse.
Purpose of the Study:
- To investigate the effectiveness of BH3 mimetics in targeting pro-survival BCL-2 proteins for rhabdomyosarcoma treatment.
- To identify and overcome anti-apoptotic adaptations induced by targeted therapies.
Main Methods:
- Utilized dynamic BH3 profiling to assess targeted agent effectiveness and adaptive resistance mechanisms.
- Examined the impact of MEK1/2 inhibitor trametinib on pro-apoptotic protein NOXA levels.
- Evaluated the synergistic cytotoxicity of trametinib combined with MCL-1 inhibitor S63845 in vitro and in vivo.
Main Results:
- Trametinib treatment led to rapid depletion of NOXA, increasing MCL-1 availability.
- The MCL-1 inhibitor S63845 synergistically enhanced trametinib-induced cytotoxicity in rhabdomyosarcoma cells.
- Combination therapy demonstrated improved efficacy in both in vitro and in vivo models.
Conclusions:
- Combining an MCL-1 targeting BH3 mimetic with trametinib effectively blocks tumor adaptation to treatment.
- This combination strategy enhances therapeutic efficiency in rhabdomyosarcoma.
- Blocking adaptive resistance mechanisms is crucial for durable remission in rhabdomyosarcoma.
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