2025 Hot Topic in Basic & Translational Science: Small Cell Lung Cancer - ePosters-EP01.13: ELAVL3 controls neuroendocrine state plasticity in small cell lung cancer through regulation of NOTCH2 signaling pathway RNA translation

EP01.13: ELAVL3 controls neuroendocrine state plasticity in small cell lung cancer through regulation of NOTCH2 signaling pathway RNA translation

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The document focuses on the role of the ELAVL3 protein in small cell lung cancer (SCLC), specifically addressing its interactions with the NOTCH2 signaling pathway, and how these influence neuroendocrine (NE) and non-NE SCLC subtype plasticity. SCLC subtype plasticity is a major contributor to acquired drug resistance, largely mediated by epigenetic factors. Previous attempts to target ASCL1 and NOTCH pathways failed to develop effective pharmacological treatments. The study introduces the "ELAVL3-NOTCH2" signaling axis as a potential target for treatment, offering a novel therapeutic approach for non-NE SCLC, which often becomes resistant to traditional treatments.<br /><br />Key findings indicate that ELAVL3 inhibitors, when combined with chemotherapy, could enhance treatment response in non-NE SCLC, whereas these inhibitors alone show anti-tumor efficacy in high NE SCLC. Additionally, ELAVL3's binding to NOTCH2 mRNA suggests a direct regulation that could alter NE/non-NE differentiation through changed RNA translation. Research highlights include tumor viability variability following ELAVL3 treatment in both SCLC and non-small cell lung cancer (NSCLC) cell lines, and the impact of subtype switching in therapy resistance, leading to reacquisition of NE characteristics and activated NOTCH2 signaling.<br /><br />The document further details experimental methods including histochemical staining, mRNA and protein expression analyses, and RNA binding assays, all of which highlight discrepancies in tumor cell viability and NE characteristics based on ELAVL3 and NOTCH2 pathway interactions. These insights support the proposal of a targeted, epigenetic therapy strategy to combat drug-resistant non-NE SCLC.<br /><br />In summary, the study underscores the potential of targeting the ELAVL3-NOTCH2 axis for developing therapies aimed at minimizing subtype shifts and improving responses in resistant SCLC cases, emphasizing its significance as a salvage treatment approach.

Asset Subtitle

Shuangsi Liao

Keywords

ELAVL3 protein

small cell lung cancer

NOTCH2 signaling

neuroendocrine plasticity

drug resistance

epigenetic factors

ELAVL3 inhibitors

chemotherapy

RNA translation

targeted therapy