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
{"title":"染色体外 DNA 扩增 MYC 对映体导致小细胞肺癌的获得性交叉耐药性。","authors":"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","doi":"10.1158/2159-8290.CD-23-0656","DOIUrl":null,"url":null,"abstract":"<p><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 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.</p><p><strong>Significance: </strong>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.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7000,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11061613/pdf/","citationCount":"0","resultStr":"{\"title\":\"Acquired Cross-Resistance in Small Cell Lung Cancer due to Extrachromosomal DNA Amplification of MYC Paralogs.\",\"authors\":\"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\",\"doi\":\"10.1158/2159-8290.CD-23-0656\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Small cell lung cancer (SCLC) presents as a highly chemosensitive malignancy but acquires cross-resistance after relapse. 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Acquired Cross-Resistance in Small Cell Lung Cancer due to Extrachromosomal DNA Amplification of MYC Paralogs.
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.
Significance: 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.
期刊介绍:
Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.