Co-targeting MCL-1 and ERK1/2 kinase induces mitochondrial apoptosis in rhabdomyosarcoma cells

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• The RAS/MEK/ERK signaling pathway is frequently dysregulated in rhabdomyosarcoma (RMS), leading to high ERK1/2 kinase activity.
• Previous studies found that inhibiting the RAS/MEK/ERK pathway alone is insufficient to cause cell death in RMS due to sustained MCL-1 activity.

Purpose of the Study:

• To investigate the synergistic effect of combining an ERK1/2 inhibitor (Ulixertinib) with an MCL-1 inhibitor (S63845) in rhabdomyosarcoma.
• To elucidate the molecular mechanisms underlying apoptosis induction by this drug combination.

Main Methods:

• In vitro and in vivo experiments using RMS cell lines and models.
• Co-treatment with Ulixertinib and S63845.
• Analysis of apoptosis markers, BCL-2 family proteins, and genetic silencing of key apoptotic factors (BIM, BMF, BAK, BAX).

Main Results:

• The combination of Ulixertinib and S63845 demonstrated high synergy, inducing significant apoptotic cell death in RMS cells both in vitro and in vivo.
• Co-treatment suppressed long-term RMS cell survival and triggered rapid caspase activation, indicating caspase-dependent apoptosis.
• Mechanistically, Ulixertinib upregulated BIM and BMF, and S63845 inhibited MCL-1, shifting the BCL-2 protein balance towards apoptosis.

Conclusions:

• Combined inhibition of ERK1/2 and MCL-1 is a highly effective strategy for inducing apoptosis in rhabdomyosarcoma.
• This approach targets the intrinsic mitochondrial apoptotic pathway and requires BIM, BMF, BAK, and BAX for maximal efficacy.
• This study presents the first evidence of the cytotoxic potential of co-targeting ERK1/2 and MCL-1 for RMS treatment.