Targeting a Chemo-Induced Adaptive Signaling Circuit Confers Therapeutic Vulnerabilities in Pancreatic Cancer

Authors

Xu Feng
Mengfan Tang
Merve Dede
Dan Su
Guangsheng Pei
Dadi Jiang
Chao Wang
Zhen Chen
Mi Li
Litong Nie
Yun Xiong
Siting Li
Jeong-Min Park
Huimin Zhang
Min Huang
Klaudia Szymonowicz
Zhongming Zhao
Traver Hart
Junjie Chen

Publication Date

5-13-2022

Journal

Science Advances

Abstract

Exploiting cancer vulnerabilities is critical for the discovery of anticancer drugs. However, tumor suppressors cannot be directly targeted because of their loss of function. To uncover specific vulnerabilities for cells with deficiency in any given tumor suppressor(s), we performed genome-scale CRISPR loss-of-function screens using a panel of isogenic knockout cells we generated for 12 common tumor suppressors. Here, we provide a comprehensive and comparative dataset for genetic interactions between the whole-genome protein-coding genes and a panel of tumor suppressor genes, which allows us to uncover known and new high-confidence synthetic lethal interactions. Mining this dataset, we uncover essential paralog gene pairs, which could be a common mechanism for interpreting synthetic lethality. Moreover, we propose that some tumor suppressors could be targeted to suppress proliferation of cells with deficiency in other tumor suppressors. This dataset provides valuable information that can be further exploited for targeted cancer therapy.

Keywords

Antineoplastic Agents, CRISPR-Cas Systems, Cell Line, Tumor, Clustered Regularly Interspaced Short Palindromic Repeats, Genes, Tumor Suppressor, Humans, Neoplasms, Synthetic Lethal Mutations

DOI

10.1126/sciadv.abm6638

PMID

35559673

PMCID

PMC9106303

PubMedCentral® Posted Date

5-13-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes