@article{dfa4c0820fc0434ca43d191661ec6d16,
title = "Lineage-coupled clonal capture identifies clonal evolution mechanisms and vulnerabilities of BRAFV600E inhibition resistance in melanoma",
abstract = "Targeted cancer therapies have revolutionized treatment but their efficacies are limited by the development of resistance driven by clonal evolution within tumors. We developed “CAPTURE”, a single-cell barcoding approach to comprehensively trace clonal dynamics and capture live lineage-coupled resistant cells for in-depth multi-omics analysis and functional exploration. We demonstrate that heterogeneous clones, either preexisting or emerging from drug-tolerant persister cells, dominated resistance to vemurafenib in BRAFV600E melanoma. Further integrative studies uncovered diverse resistance mechanisms. This includes a previously unrecognized and clinically relevant mechanism, chromosome 18q21 gain, which leads to vulnerability of the cells to BCL2 inhibitor. We also identified targetable common dependencies of captured resistant clones, such as oxidative phosphorylation and E2F pathways. Our study provides new therapeutic insights into overcoming therapy resistance in BRAFV600E melanoma and presents a platform for exploring clonal evolution dynamics and vulnerabilities that can be applied to study treatment resistance in other cancers.",
author = "Zhang, {Ze Yan} and Yingwen Ding and Ravesanker Ezhilarasan and Tenzin Lhakhang and Qianghu Wang and Jie Yang and Modrek, {Aram S.} and Hua Zhang and Aristotelis Tsirigos and Andrew Futreal and Draetta, {Giulio F.} and Verhaak, {Roel G.W.} and Sulman, {Erik P.}",
note = "Funding Information: We thank Andrea Viale and Alessandro Carugo at the University of Texas MD Anderson Cancer Center (MDACC) for helpful discussion; Ying Hu at the National Institutes of Health/National Cancer Institute (NIH/NCI) for help in adjusting the Circos plot parameters. We thank Jerome Karp at NYU Langone Health for proofreading. Next-generation sequencing was performed by the NYU Langone Genome Technology Center, which is supported in part by grant P30CA016087 from NIH/NCI. Cell sorting/flow cytometry technologies were provided by NYU Langone{\textquoteright}s Cytometry and Cell Sorting Laboratory (supported in part by grant P30CA016087) and the MDACC Flow Cytometry and Cellular Imaging Core Facility (supported by NCI grant P30CA16672). STR DNA fingerprinting was done by the Cancer Center Support Grant-funded Characterized Cell Line core (supported by NCI grant CA016672). This study was supported by R01 CA190121-01 (Z.-Y.Z., R.G.W.V., and E.P.S.) and by the DefeatGBM collaborative of the National Brain Tumor Association (Q.W. and E.P.S.). Funding Information: We thank Andrea Viale and Alessandro Carugo at the University of Texas MD Anderson Cancer Center (MDACC) for helpful discussion; Ying Hu at the National Institutes of Health/National Cancer Institute (NIH/NCI) for help in adjusting the Circos plot parameters. We thank Jerome Karp at NYU Langone Health for proofreading. Next-generation sequencing was performed by the NYU Langone Genome Technology Center, which is supported in part by grant P30CA016087 from NIH/NCI. Cell sorting/flow cytometry technologies were provided by NYU Langone{\textquoteright}s Cytometry and Cell Sorting Laboratory (supported in part by grant P30CA016087) and the MDACC Flow Cytometry and Cellular Imaging Core Facility (supported by NCI grant P30CA16672). STR DNA fingerprinting was done by the Cancer Center Support Grant-funded Characterized Cell Line core (supported by NCI grant CA016672). This study was supported by R01 CA190121-01 (Z.-Y.Z., R.G.W.V., and E.P.S.) and by the DefeatGBM collaborative of the National Brain Tumor Association (Q.W. and E.P.S.). Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = dec,
doi = "10.1038/s41421-022-00462-7",
language = "English (US)",
volume = "8",
journal = "Cell Discovery",
issn = "2056-5968",
publisher = "Nature Publishing Group",
number = "1",
}