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  3. Lineage-coupled clonal capture identifies clonal evolution mechanisms and vulnerabilities of BRAFV600E inhibition resistance in melanoma

Lineage-coupled clonal capture identifies clonal evolution mechanisms and vulnerabilities of BRAFV600E inhibition resistance in melanoma

  • Cell Discov. 2022 Oct 6;8(1):102. doi: 10.1038/s41421-022-00462-7.
Ze-Yan Zhang 1 2,  Yingwen Ding 3 4,  Ravesanker Ezhilarasan 3 4,  Tenzin Lhakhang 5,  Qianghu Wang 6 7 8,  Jie Yang 3 4,  Aram S Modrek 3 4,  Hua Zhang 9,  Aristotelis Tsirigos 5,  Andrew Futreal 10,  Giulio F Draetta 10,  Roel G W Verhaak 11,  Erik P Sulman 12 13
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, New York University (NYU) Grossman School of Medicine, New York, NY, USA. zeyan.zhang@nyulangone.org.
  • 2 Brain and Spine Tumor Center, Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA. zeyan.zhang@nyulangone.org.
  • 3 Department of Radiation Oncology, New York University (NYU) Grossman School of Medicine, New York, NY, USA.
  • 4 Brain and Spine Tumor Center, Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.
  • 5 Applied Bioinformatics Laboratories, NYU Grossman School of Medicine, New York, NY, USA.
  • 6 Department of Bioinformatics, Nanjing Medical University, Nanjing, Jiangsu, China.
  • 7 Institute for Brain Tumors, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.
  • 8 Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing, Jiangsu, China.
  • 9 Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.
  • 10 Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 11 Department of Computational Biology, The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
  • 12 Department of Radiation Oncology, New York University (NYU) Grossman School of Medicine, New York, NY, USA. erik.sulman@nyulangone.org.
  • 13 Brain and Spine Tumor Center, Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA. erik.sulman@nyulangone.org.
PMID: 36202798 DOI: 10.1038/s41421-022-00462-7
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.

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