Acquired Cross-Resistance in Small Cell Lung Cancer due to Extrachromosomal DNA Amplification of MYC Paralogs.

Autor:	Pal Choudhuri S; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas.; Department of Internal Medicine and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas., Girard L; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas.; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas., Lim JYS; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas., Wise JF; Massachusetts General Hospital Cancer Center, Krantz Family Center for Cancer Research, Harvard Medical School, Boston, Massachusetts.; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Broad Institute of Harvard and MIT, Cambridge, Massachusetts., Freitas B; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas.; Department of Internal Medicine and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas., Yang D; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas.; Department of Internal Medicine and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas., Wong E; Massachusetts General Hospital Cancer Center, Krantz Family Center for Cancer Research, Harvard Medical School, Boston, Massachusetts., Hamilton S; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas.; Department of Internal Medicine and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas., Chien VD; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas.; Department of Internal Medicine and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas., Kim YJ; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas., Gilbreath C; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas., Zhong J; Massachusetts General Hospital Cancer Center, Krantz Family Center for Cancer Research, Harvard Medical School, Boston, Massachusetts., Phat S; Massachusetts General Hospital Cancer Center, Krantz Family Center for Cancer Research, Harvard Medical School, Boston, Massachusetts., Myers DT; Massachusetts General Hospital Cancer Center, Krantz Family Center for Cancer Research, Harvard Medical School, Boston, Massachusetts., Christensen CL; Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts., Mazloom-Farsibaf H; Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, Texas., Stanzione M; Massachusetts General Hospital Cancer Center, Krantz Family Center for Cancer Research, Harvard Medical School, Boston, Massachusetts., Wong KK; Perlmutter Cancer Center, NYU Langone Health, New York, New York., Hung YP; Massachusetts General Hospital Cancer Center, Krantz Family Center for Cancer Research, Harvard Medical School, Boston, Massachusetts.; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Farago AF; Massachusetts General Hospital Cancer Center, Krantz Family Center for Cancer Research, Harvard Medical School, Boston, Massachusetts., Meador CB; Massachusetts General Hospital Cancer Center, Krantz Family Center for Cancer Research, Harvard Medical School, Boston, Massachusetts., Dyson NJ; Massachusetts General Hospital Cancer Center, Krantz Family Center for Cancer Research, Harvard Medical School, Boston, Massachusetts., Lawrence MS; Massachusetts General Hospital Cancer Center, Krantz Family Center for Cancer Research, Harvard Medical School, Boston, Massachusetts.; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Broad Institute of Harvard and MIT, Cambridge, Massachusetts., Wu S; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas., Drapkin BJ; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas.; Department of Internal Medicine and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2024 May 01; Vol. 14 (5), pp. 804-827.
DOI:	10.1158/2159-8290.CD-23-0656
Abstrakt:	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. (©2024 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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