Unique vulnerability of RAC1-mutant melanoma to combined inhibition of CDK9 and immune checkpoints

Author:

Chernoff Jonathan1,Cannon Alexa1,Budagyan Konstantin1,Uribe-Alvarez Cristina1,Kurimchak Alison2,Araiza-Olivera Daniela,Peri Suraj2,Zhou Yan3ORCID,Cai Kathy2,Duncan James2

Affiliation:

1. Fox Chase Cancer Center, Philadelphia

2. Fox Chase Cancer Center

3. Fox Chase Cancer Center, Philadelphia, Pennsylvania

Abstract

Abstract RAC1 P29S is the third most prevalent hotspot mutation in sun-exposed melanoma. RAC1 alterations in cancer are correlated with poor prognosis, resistance to standard chemotherapy, and insensitivity to targeted inhibitors. Although RAC1P29S mutations in melanoma and RAC1 alterations in several other cancers are increasingly evident, the RAC1-driven biological mechanisms contributing to tumorigenesis remain unclear. Lack of rigorous signaling analysis has prevented identification of alternative therapeutic targets for RAC1P29S-harboring melanomas. To investigate the RAC1P29S-driven effect on downstream molecular signaling pathways, we generated an inducible RAC1P29S expression melanocytic cell line and performed RNA-sequencing (RNA-seq) coupled with multiplexed kinase inhibitor beads and mass spectrometry (MIBs/MS) to establish enriched pathways from the genomic to proteomic level. Our proteogenomic analysis identified CDK9 as a potential new and specific target in RAC1P29S-mutant melanoma cells. In vitro, CDK9 inhibition impeded the proliferation of in RAC1P29S-mutant melanoma cells and increased surface expression of PD-L1 and MHC Class I proteins. In vivo, combining CDK9 inhibition with anti-PD-1 immune checkpoint blockade significantly inhibited tumor growth only in melanomas that expressed the RAC1P29S mutation. Collectively, these results establish CDK9 as a novel target in RAC1-driven melanoma that can further sensitize the tumor to anti-PD-1 immunotherapy.

Publisher

Research Square Platform LLC

Reference48 articles.

1. A landscape of driver mutations in melanoma;Hodis E;Cell,2012

2. Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma;Krauthammer M;Nat Genet,2012

3. RAC1P29S is a spontaneously activating cancer-associated GTPase;Davis MJ;Proc Natl Acad Sci U S A,2013

4. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data;Cerami E;Cancer Discov,2012

5. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal;Gao J;Sci Signal,2013

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3