Single-cell Genomics Analysis Reveals Complex Genetic Interactions in an Model of Acquired BRAF Inhibitor Resistance

Overview

Journal NAR Cancer

Publisher Oxford University Press

Specialty Oncology

Date 2024 Jan 12

PMID 38213996

Authors

Jacob L Schillo

Charlotte R Feddersen

Rebekah M Peplinski

Lexy S Powell

Afshin Varzavand

Christopher S Stipp

Jesse D Riordan

Adam J Dupuy

Affiliations

Soon will be listed here.

Abstract

The evolution of therapeutic resistance is a major obstacle to the success of targeted oncology drugs. While both inter- and intratumoral heterogeneity limit our ability to detect resistant subpopulations that pre-exist or emerge during treatment, our ability to analyze tumors with single-cell resolution is limited. Here, we utilized a cell-based transposon mutagenesis method to identify mechanisms of BRAF inhibitor resistance in a model of cutaneous melanoma. This screen identified overexpression of NEDD4L and VGLL3 as significant drivers of BRAF inhibitor resistance . In addition, we describe a novel single-cell genomics profiling method to genotype thousands of individual cells within tumors driven by transposon mutagenesis. This approach revealed a surprising genetic diversity among xenograft tumors and identified recurrent co-occurring mutations that emerge within distinct tumor subclones. Taken together, these observations reveal an unappreciated genetic complexity that drives BRAF inhibitor resistance.

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