Sensitization to Ionizing Radiation by MEK inhibition is Dependent on SNAI2 in Fusion-negative Rhabdomyosarcoma.
Nicole Rae HenschKathryn M BondraLong WangPrethish SreenivasXiang Ru ZhaoPaulomi ModiAngelina V VasevaPeter J HoughtonMyron S IgnatiusPublished in: Molecular cancer therapeutics (2022)
In fusion-negative rhabdomyosarcoma (FN-RMS), a pediatric malignancy with skeletal muscle characteristics, > 90% of high-risk patients have mutations that activate the RAS/MEK signaling pathway. We recently discovered that SNAI2, in addition to blocking myogenic differentiation downstream of MEK signaling in FN-RMS, represses pro-apoptotic BIM expression to protect RMS tumors from ionizing radiation (IR). As clinically relevant concentrations of the MEK inhibitor trametinib elicit poor responses in preclinical xenograft models, we investigated the utility of low-dose trametinib in combination with IR for the treatment of RAS-mutant FN-RMS. We hypothesized that trametinib would sensitize FN-RMS to IR through its downregulation of SNAI2 expression. While we observed little to no difference in myogenic differentiation or cell survival with trametinib treatment alone, robust differentiation and reduced survival were observed after IR. Additionally, IR-induced apoptosis was significantly increased in FN-RMS cells treated concurrently with trametinib, as was increased BIM expression. SNAI2's role in these processes was established using overexpression rescue experiments, where overexpression of SNAI2 prevented IR-induced myogenic differentiation and apoptosis. Moreover, combining MEK inhibitor with IR resulted in complete tumor regression and a 2-4-week delay in event free survival (EFS) in preclinical xenograft and patient-derived xenograft models. Our findings demonstrate that the combination of MEK inhibition and IR results in robust differentiation and apoptosis, due to the reduction of SNAI2, which leads to extended EFS in FN-RMS. SNAI2 thus is a potential biomarker of IR insensitivity and target for future therapies to sensitize aggressive sarcomas to IR.
Keyphrases
- induced apoptosis
- pi k akt
- signaling pathway
- skeletal muscle
- endoplasmic reticulum stress
- cell cycle arrest
- oxidative stress
- low dose
- poor prognosis
- free survival
- cell proliferation
- cell death
- end stage renal disease
- newly diagnosed
- high dose
- binding protein
- type diabetes
- randomized controlled trial
- mesenchymal stem cells
- high resolution
- mass spectrometry
- stem cells
- current status
- long non coding rna
- bone marrow
- cell therapy
- peritoneal dialysis
- adipose tissue
- high grade
- smoking cessation