Data from Acquired Cross-Resistance in Small Cell Lung Cancer due to Extrachromosomal DNA Amplification of <i>MYC</i> Paralogs

• DOI: 10.1158/2159-8290.c.7209241.v1
• Publication Date: 2024-05-01T14:14:21Z
• Authors: Shreoshi Pal Chou...; 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. Christ...; Hanieh Mazloom-Fa...; 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

<div>Abstract<p>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 <i>in vivo</i> 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 <i>MYC</i> amplification on extrachromosomal DNA (ecDNA). Genomic and transcriptional profiles of the full PDX panel revealed that <i>MYC</i> 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 <i>MYC</i> paralogs are recurrent drivers of cross-resistance in SCLC.</p>Significance:<p>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 <i>MYC</i> paralogs on ecDNA are recurrent drivers of acquired cross-resistance in SCLC.</p><p><i><a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-14-5-ITI" target="_blank">This article is featured in Selected Articles from This Issue, p. 695</a></i></p></div>