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Updated: Jul 24, 2025

Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
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Acquired Cross-resistance in Small Cell Lung Cancer due to Extrachromosomal DNA Amplification of MYC paralogs

Shreoshi Pal Choudhuri, Luc Girard, Jun Yi Stanley Lim

    Biorxiv : the Preprint Server for Biology
    |July 10, 2023
    PubMed

    Insights

    Small cell lung cancer (SCLC) initially responds to chemotherapy but develops resistance. Researchers discovered that amplified MYC paralogs on extrachromosomal DNA (ecDNA) drive this acquired cross-resistance in SCLC models.

    Area of Science:

    • Oncology
    • Genomics
    • Cancer Biology

    Background:

    • Small cell lung cancer (SCLC) is highly chemosensitive but inevitably acquires cross-resistance upon relapse.
    • Understanding the genomic drivers of acquired cross-resistance in SCLC is crucial for developing effective treatments.

    Approach:

    • Developed a pre-clinical system using 51 patient-derived xenografts (PDXs) to model SCLC acquired cross-resistance.
    • Tested PDX models for in vivo sensitivity to cisplatin/etoposide, olaparib/temozolomide, and topotecan.
    • Utilized genomic and transcriptional profiling to identify mechanisms of resistance.

    Key Points:

    • Acquired cross-resistance in SCLC was recapitulated in patient-derived xenograft models.
    • MYC amplification on extrachromosomal DNA (ecDNA) was identified as a key mechanism of resistance in serially derived PDX models.
    • Recurrent amplifications of MYC paralogs on ecDNAs were observed in cross-resistant SCLC models from multiple patients.

    Conclusions:

    • Extrachromosomal DNA (ecDNA) carrying MYC paralog amplifications are recurrent drivers of acquired cross-resistance in SCLC.
    • This discovery provides a potential therapeutic target for overcoming treatment resistance in SCLC.

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