title: Studying clonal dynamics in response to cancer therapy using high-complexity barcoding.
abstract: Resistance to cancer therapies presents a significant clinical challenge. Recent studies have revealed intratumoral heterogeneity as a source of therapeutic resistance. However, it is unclear whether resistance is driven predominantly by pre-existing or de novo alterations, in part because of the resolution limits of next-generation sequencing. To address this, we developed a high-complexity barcode library, ClonTracer, which enables the high-resolution tracking of more than 1 million cancer cells under drug treatment. In two clinically relevant models, ClonTracer studies showed that the majority of resistant clones were part of small, pre-existing subpopulations that selectively escaped under therapeutic challenge. Moreover, the ClonTracer approach enabled quantitative assessment of the ability of combination treatments to suppress resistant clones. These findings suggest that resistant clones are present before treatment, which would make up-front therapeutic combinations that target non-overlapping resistance a preferred approach. Thus, ClonTracer barcoding may be a valuable tool for optimizing therapeutic regimens with the goal of curative combination therapies for cancer.
authors: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors: Hyo-eun C
authors: 0000000318927093
authors: HE
authors: Bhang
authors: Translational Clinical Oncology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors: David A
authors: DA
authors: Ruddy
authors: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors: Viveksagar
authors: V
authors: Krishnamurthy Radhakrishna
authors: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors: Justina X
authors: JX
authors: Caushi
authors: 1] Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA.
authors: Rui
authors: R
authors: Zhao
authors: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors: Matthew M
authors: MM
authors: Hims
authors: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors: Angad P
authors: AP
authors: Singh
authors: Translational Clinical Oncology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors: Iris
authors: I
authors: Kao
authors: Translational Clinical Oncology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors: Daniel
authors: D
authors: Rakiec
authors: Translational Clinical Oncology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors: Pamela
authors: P
authors: Shaw
authors: Translational Clinical Oncology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors: Marissa
authors: M
authors: Balak
authors: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors: Alina
authors: A
authors: Raza
authors: Translational Clinical Oncology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors: Elizabeth
authors: 0000000212043951
authors: E
authors: Ackley
authors: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors: Nicholas
authors: N
authors: Keen
authors: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors: Michael R
authors: MR
authors: Schlabach
authors: Translational Clinical Oncology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors: Michael
authors: M
authors: Palmer
authors: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors: Rebecca J
authors: RJ
authors: Leary
authors: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors: Derek Y
authors: DY
authors: Chiang
authors: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors: William R
authors: WR
authors: Sellers
authors: 1] Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA.
authors: Franziska
authors: F
authors: Michor
authors: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors: Vesselina G
authors: VG
authors: Cooke
authors: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors: Joshua M
authors: JM
authors: Korn
authors: Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors: Frank
authors: F
authors: Stegmeier
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D000077547:Crizotinib; D004247:DNA / Q000737:chemistry; D058893:DNA Barcoding, Taxonomic / Q000379:methods*; D018076:DNA, Complementary / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D000069347:Erlotinib Hydrochloride; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D018628:Gene Dosage; D015723:Gene Library; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics; D008962:Models, Theoretical; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D009841:Oligonucleotides / Q000235:genetics; D016133:Polymerase Chain Reaction; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage; D017423:Sequence Analysis, RNA
chemical_list: C581634:BCR-ABL1 fusion protein, human; D018076:DNA, Complementary; D009841:Oligonucleotides; D011720:Pyrazoles; D011725:Pyridines; D011799:Quinazolines; D000077547:Crizotinib; D004247:DNA; D000069347:Erlotinib Hydrochloride; D019859:Proto-Oncogene Proteins c-met; D016044:Fusion Proteins, bcr-abl; D016315:Proto-Oncogene Proteins c-abl