Lineage-Coupled Clonal Capture Identifies Clonal Evolution Mechanisms and Vulnerabilities of BRAF V600E Inhibition Resistance in Melanoma

Authors

Ze-Yan Zhang
Yingwen Ding
Ravesanker Ezhilarasan
Tenzin Lhakhang
Qianghu Wang
Jie Yang
Aram S Modrek
Hua Zhang
Aristotelis Tsirigos
Andrew Futreal
Giulio F Draetta
Roel G W Verhaak
Erik P Sulman

Publication Date

10-6-2022

Journal

Cell Discovery

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.

Keywords

Melanoma, Tumour heterogeneity

Comments

Supplementary Materials

PMID: 36202798