TY - JOUR
T1 - ER stress signaling promotes the survival of cancer "Persister Cells" tolerant to EGFR tyrosine Kinase inhibitors
AU - Terai, Hideki
AU - Kitajima, Shunsuke
AU - Potter, Danielle S.
AU - Matsui, Yusuke
AU - Quiceno, Laura Gutierrez
AU - Chen, Ting
AU - Kim, Tae Jung
AU - Rusan, Maria
AU - Thai, Tran C.
AU - Piccioni, Federica
AU - Donovan, Katherine A.
AU - Kwiatkowski, Nicholas
AU - Hinohara, Kunihiko
AU - Wei, Guo
AU - Gray, Nathanael S.
AU - Fischer, Eric S.
AU - Wong, Kwok Kin
AU - Shimamura, Teppei
AU - Letai, Anthony
AU - Hammerman, Peter S.
AU - Barbie, David A.
N1 - Funding Information:
This work was supported by NCI-P01 CA154303 (to P.S. Hammerman), NCI-R01 CA19632-02 (to P.S. Hammerman), NCI-R01 CA190394-01 (to D.A. Barbie), the Schaubert, Gloria T. Maheu, and Heerwagen Family Funds for Lung Cancer Research (to D.A. Barbie), NCI-R01 CA179483 (to N.S. Gray), and Lilly oncology fellowship (to H.Terai).
Funding Information:
N.S. Gray has ownership interest (including patents) and is a consultant/ advisory board member for Syros. A. Letai reports receiving a commercial research grant from AbbVie, AstraZeneca, and Novartis. D.A. Barbie is a consultant for N-of-One. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
We are grateful to P. Choi, Y. Mitsuishi, for providing materials, technical instruction and useful discussion, and Molecular Biology Core Facilities at Dana-Farber Cancer Institute for the preparation and sequencing of RNA-seq. This work was supported by NCI-P01 CA154303 (to P.S. Hammerman), NCI-R01 CA19632-02 (to P.S. Hammerman), NCI-R01 CA190394-01 (to D.A. Barbie), the Schaubert, Gloria T. Maheu, and Heerwagen Family Funds for Lung Cancer Research (to D.A. Barbie), NCI-R01 CA179483 (to N.S. Gray), and Lilly oncology fellowship (to H.Terai).
Publisher Copyright:
© 2017 American Association for Cancer Research.
PY - 2018/2/15
Y1 - 2018/2/15
N2 - An increasingly recognized component of resistance to tyrosine kinase inhibitors (TKI) involves persistence of a drug-tolerant subpopulation of cancer cells that survive despite effective eradication of the majority of the cell population. Multiple groups have demonstrated that these drug-tolerant persister cells undergo transcriptional adaptation via an epigenetic state change that promotes cell survival. Because this mode of TKI drug tolerance appears to involve transcriptional addiction to specific genes and pathways, we hypothesized that systematic functional screening of EGFR TKI/transcriptional inhibitor combination therapy would yield important mechanistic insights and alternative drug escape pathways. We therefore performed a genome-wide CRISPR/Cas9 enhancer/suppressor screen in EGFR-dependent lung cancer PC9 cells treated with erlotinib þ THZ1 (CDK7/12 inhibitor) combination therapy, a combination previously shown to suppress drug-tolerant cells in this setting. As expected, suppression of multiple genes associated with transcriptional complexes (EP300, CREBBP, and MED1) enhanced erlotinib/THZ1 synergy. Unexpectedly, we uncovered nearly every component of the recently described ufmylation pathway in the synergy suppressor group. Loss of ufmylation did not affect canonical downstream EGFR signaling. Instead, absence of this pathway triggered a protective unfolded protein response associated with STING upregulation, promoting protumorigenic inflammatory signaling but also unique dependence on Bcl-xL. These data reveal that dysregulation of ufmylation and ER stress comprise a previously unrecognized TKI drug tolerance pathway that engages survival signaling, with potentially important therapeutic implications.
AB - An increasingly recognized component of resistance to tyrosine kinase inhibitors (TKI) involves persistence of a drug-tolerant subpopulation of cancer cells that survive despite effective eradication of the majority of the cell population. Multiple groups have demonstrated that these drug-tolerant persister cells undergo transcriptional adaptation via an epigenetic state change that promotes cell survival. Because this mode of TKI drug tolerance appears to involve transcriptional addiction to specific genes and pathways, we hypothesized that systematic functional screening of EGFR TKI/transcriptional inhibitor combination therapy would yield important mechanistic insights and alternative drug escape pathways. We therefore performed a genome-wide CRISPR/Cas9 enhancer/suppressor screen in EGFR-dependent lung cancer PC9 cells treated with erlotinib þ THZ1 (CDK7/12 inhibitor) combination therapy, a combination previously shown to suppress drug-tolerant cells in this setting. As expected, suppression of multiple genes associated with transcriptional complexes (EP300, CREBBP, and MED1) enhanced erlotinib/THZ1 synergy. Unexpectedly, we uncovered nearly every component of the recently described ufmylation pathway in the synergy suppressor group. Loss of ufmylation did not affect canonical downstream EGFR signaling. Instead, absence of this pathway triggered a protective unfolded protein response associated with STING upregulation, promoting protumorigenic inflammatory signaling but also unique dependence on Bcl-xL. These data reveal that dysregulation of ufmylation and ER stress comprise a previously unrecognized TKI drug tolerance pathway that engages survival signaling, with potentially important therapeutic implications.
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UR - http://www.scopus.com/inward/citedby.url?scp=85042176157&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-17-1904
DO - 10.1158/0008-5472.CAN-17-1904
M3 - Article
C2 - 29259014
AN - SCOPUS:85042176157
VL - 78
SP - 1044
EP - 1057
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 4
ER -