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. 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
Acquired ecMYCN amplification in MGH1578 serial models and lineage oncogene expression compared with ecDNA status across the PDX panel.
Reconstruction of ecDNAs containing MYC paralogs and MYCL FISH in MGH1501-1A metaphase chromosomes.
MYC paralog copy number and ecDNA status in SCLC cell lines, PDX models and biopsy samples derived before treatment or after relapse.
MYC paralog amplifications that were detected or omitted by segmented copy number analysis, and patient survival compared with ecDNA status of PDX models.
Genomic analysis of chromosome 17 focal amplification in MGH1531-5BX and analysis of ecDNA junction mutations in MGH1518-3A.
Supplementary Figure S8. KRASG12C and SHP2 inhibition does not inhibit the growth of signaling of a non-KRASG12C mutant cell line.
Supplementary Figure S7. SHP2 inhibition enhances the efficacy of KRASG12C inhibition.
Supplementary Figure S6. SHP2 inhibition enhances suppression of MAPK signaling in the presence of KRASG12C inhibition.
Supplementary Figure S3. RTK inhibitors display variable cooperative effects with KRASG12C inhibitors across models.
Sarah Phat合作论文数34Benjamin J Drapkin合作论文数25
Anna F. Farago合作论文数Massachusetts General Hospital Cancer Center and Harvard Medical School,Boston24Nicholas J. Dyson合作论文数24Jun Zhong合作论文数23Edmond Wong合作论文数21
Michael S. Lawrence合作论文数Harvard Medical School;Lawrence Laboratory, Mass General Cancer Center, Massachusetts General Hospital19
Marcello Stanzione合作论文数Tech Univ Dresden, Fac Med, Inst Physiol Chem, Fetscherstr 74, D-01307 Dresden, Germany18Christensen Camilla L合作论文数16
Rex Hung合作论文数Department of Pathology, Massachusetts General Hospital16
Wise Jillian F合作论文数Univ Texas MD Anderson Canc Ctr14Hanieh Mazloom-Farsibaf合作论文数13Victor D. Chien合作论文数13Seth Hamilton合作论文数13Braeden Freitas合作论文数13
Sihan Wu合作论文数13Shreoshi Pal Choudhuri合作论文数University of Texas Southwestern Medical Center13Collin Gilbreath合作论文数13Di Yang合作论文数13Jun Yi Stanley Lim合作论文数13
Kwok-Kin Wong合作论文数Department of Medicine, Grossman School of Medicine, New York University13Meador Catherine B合作论文数13
Luc Girard合作论文数Department of Hamon Center for Therapeutic Oncology Research, Medical School, University of Texas Southwestern Medical Center;Department of Pharmacology, University of Texas Southwestern Medical Center13
Jung-Whan Kim合作论文数Department of Toxicology, National Institute of Toxicological Research13Heather A. Shahzade合作论文数9Catriona B Hong合作论文数9
Ferran Fece de la Cruz合作论文数9
Meagan B. Ryan合作论文数University of North Carolina, University of North Carolina at Chapel Hill9Aaron N. Hata合作论文数Massachusetts General Hospital Cancer Center/Department of Medicine, Harvard Medical School9
Ryan B. Corcoran合作论文数Department of Medicine, Harvard Medical School9
Daniel Arie Haber合作论文数Harvard Medical School;Medicine-MGH Cancer Center, Massachusetts General Hospital8
Shyamala Maheswaran合作论文数Harvard Medical School, Harvard University;Mass General Research Institute, Massachusetts General Hospital8
Alice Shaw合作论文数Harvard Medical School;Department of Medical Oncology, Dana-Farber Cancer Institute7Marina Kem合作论文数6
Lecia Sequist合作论文数Cancer Early Detection and Diagnostics Clinic, Massachusetts General Hospital Cancer Center;Harvard Medical School;Dana-Farber Cancer Center6
Gomez-Caraballo Maria合作论文数Department of Medicine and Harvard Medical School, Massachusetts General Hospital Cancer Center5
Beow Yeap合作论文数Cancer Center, Massachusetts General Hospital;Massachusetts General Hospital Biostatistics;Harvard Medical School5
Mari Mino-Kenudson合作论文数Harvard Medical School;Massachusetts General Hospital4Lee Dana合作论文数4
David Barbie合作论文数Department of Medical Oncology, Dana-Farber Cancer Institute4
Cyril H Benes合作论文数Massachusetts General Hospital Cancer Center and Harvard Medical School/Department of Medicine, Harvard Medical School4Joseph A LiCausi合作论文数3Jackson P Fatherree合作论文数3
Max Greenberg合作论文数3
J. Paul Marcoux合作论文数3Samantha J Bilton合作论文数3Giovanna T Stein合作论文数3Regina K Egan合作论文数3Eliane Cortez合作论文数3
