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Supplementary Figure S12 from Acquired Cross-Resistance in Small Cell Lung Cancer due to Extrachromosomal DNA Amplification of MYC Paralogs

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posted on 2024-05-01, 07:42 authored by Shreoshi Pal Choudhuri, Luc Girard, Jun Yi Stanley Lim, Jillian F. Wise, Braeden Freitas, Di Yang, Edmond Wong, Seth Hamilton, Victor D. Chien, Yoon Jung Kim, Collin Gilbreath, Jun Zhong, Sarah Phat, David T. Myers, Camilla L. Christensen, Hanieh Mazloom-Farsibaf, Marcello Stanzione, Kwok-Kin Wong, Yin P. Hung, Anna F. Farago, Catherine B. Meador, Nicholas J. Dyson, Michael S. Lawrence, Sihan Wu, Benjamin J. Drapkin

Acquired ecMYCN amplification in MGH1578 serial models and lineage oncogene expression compared with ecDNA status across the PDX panel.

Funding

National Cancer Institute (NCI)

United States Department of Health and Human Services

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Cancer Prevention and Research Institute of Texas (CPRIT)

Cancer Research UK Therapeutic Discovery Laboratories (CRUK-TDL)

National Institute of General Medical Sciences (NIGMS)

United States Department of Health and Human Services

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ARTICLE ABSTRACT

Small cell lung cancer (SCLC) presents as a highly chemosensitive malignancy but acquires cross-resistance after relapse. This transformation is nearly inevitable in patients but has been difficult to capture in laboratory models. Here, we present a preclinical system that recapitulates acquired cross-resistance, developed from 51 patient-derived xenograft (PDX) models. Each model was tested in vivo against three clinical regimens: cisplatin plus etoposide, olaparib plus temozolomide, and topotecan. These drug-response profiles captured hallmark clinical features of SCLC, such as the emergence of treatment-refractory disease after early relapse. For one patient, serial PDX models revealed that cross-resistance was acquired through MYC amplification on extrachromosomal DNA (ecDNA). Genomic and transcriptional profiles of the full PDX panel revealed that MYC paralog amplifications on ecDNAs were recurrent in relapsed cross-resistant SCLC, and this was corroborated in tumor biopsies from relapsed patients. We conclude that ecDNAs with MYC paralogs are recurrent drivers of cross-resistance in SCLC. SCLC is initially chemosensitive, but acquired cross-resistance renders this disease refractory to further treatment and ultimately fatal. The genomic drivers of this transformation are unknown. We use a population of PDX models to discover that amplifications of MYC paralogs on ecDNA are recurrent drivers of acquired cross-resistance in SCLC.This article is featured in Selected Articles from This Issue, p. 695

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    Cancer Discovery

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    Keywords

    ChemotherapyDna Damage And RepairDrug ResistanceClinical drug resistanceLung CancerPreclinical ModelsTranslational ResearchTumor Evolution

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