@article{a0252ed5d8f44753b5201bba77aee11b,
title = "RUVBL1/RUVBL2 ATPase Activity Drives PAQosome Maturation, DNA Replication and Radioresistance in Lung Cancer",
abstract = "RUVBL1 and RUVBL2 (collectively RUVBL1/2) are essential AAA+ ATPases that function as co-chaperones and have been implicated in cancer. Here we investigated the molecular and phenotypic role of RUVBL1/2 ATPase activity in non-small cell lung cancer (NSCLC). We find that RUVBL1/2 are overexpressed in NSCLC patient tumors, with high expression associated with poor survival. Utilizing a specific inhibitor of RUVBL1/2 ATPase activity, we show that RUVBL1/2 ATPase activity is necessary for the maturation or dissociation of the PAQosome, a large RUVBL1/2-dependent multiprotein complex. We also show that RUVBL1/2 have roles in DNA replication, as inhibition of its ATPase activity can cause S-phase arrest, which culminates in cancer cell death via replication catastrophe. While in vivo pharmacological inhibition of RUVBL1/2 results in modest antitumor activity, it synergizes with radiation in NSCLC, but not normal cells, an attractive property for future preclinical development. Yenerall et al. identified a specific inhibitor of RUVBL1/2 ATPase activity, compound B, and demonstrate that RUVBL1/2 ATPase activity is required for PAQosome maturation/dissociation. Compound B kills non-small cell lung cancer (NSCLC) by inhibiting DNA replication. In addition, compound B radiosensitizes NSCLC, but not normal cells, an attractive property for future development.",
keywords = "DNA replication, RUVBL1, RUVBL2, non-small cell lung cancer, radiation therapy",
author = "Paul Yenerall and Das, {Amit K.} and Shan Wang and Kollipara, {Rahul K.} and Li, {Long Shan} and Pamela Villalobos and Josiah Flaming and Lin, {Yu Fen} and Kenneth Huffman and Timmons, {Brenda C.} and Collin Gilbreath and Rajni Sonavane and Kinch, {Lisa N.} and Jaime Rodriguez-Canales and Cesar Moran and Carmen Behrens and Makoto Hirasawa and Takehiko Takata and Ryo Murakami and Koichi Iwanaga and Chen, {Benjamin P.C.} and Grishin, {Nick V.} and Raj, {Ganesh V.} and Wistuba, {Ignacio I.} and Minna, {John D.} and Ralf Kittler",
note = "Funding Information: We would like to thank Caroline Humphries, David Mangelsdorf, the Proteomics, Tissue Resource (supported by NCI grant 5P30CA142543 ), McDermott Sequencing, and Moody Foundation Flow Cytometry cores, as well as the Animal Resources Center, at UT Southwestern, and the Taplin Mass Spectrometry core at Harvard Medical School, for their technical assistance. We also thank Chelsea Burroughs for generating graphics. This study was supported by the Simmons Comprehensive Cancer Center at UT Southwestern (developmental funds to R.K.) and grants from CPRIT ( RP120732-C1 to I.W., RP120732-P1 to J.M., RP170170 to N.V.G., and RP120732-P3 to R.K.), the National Institutes of Health (NCI SPORE in lung cancer 5P50CA070907 to J.M., NIGMS GM127390 to N.V.G., and R01CA223828 and R01CA246433 to G.V.R.) and the Department of Defense ( W81XWH-17-1-0674 to G.V.R.). R.K. is a John L. Roach Scholar in Biomedical Research and a CPRIT Scholar in Cancer Research. Funding Information: We would like to thank Caroline Humphries, David Mangelsdorf, the Proteomics, Tissue Resource (supported by NCI grant 5P30CA142543), McDermott Sequencing, and Moody Foundation Flow Cytometry cores, as well as the Animal Resources Center, at UT Southwestern, and the Taplin Mass Spectrometry core at Harvard Medical School, for their technical assistance. We also thank Chelsea Burroughs for generating graphics. This study was supported by the Simmons Comprehensive Cancer Center at UT Southwestern (developmental funds to R.K.) and grants from CPRIT (RP120732-C1 to I.W. RP120732-P1 to J.M. RP170170 to N.V.G. and RP120732-P3 to R.K.), the National Institutes of Health (NCI SPORE in lung cancer 5P50CA070907 to J.M. NIGMS GM127390 to N.V.G. and R01CA223828 and R01CA246433 to G.V.R.) and the Department of Defense (W81XWH-17-1-0674 to G.V.R.). R.K. is a John L. Roach Scholar in Biomedical Research and a CPRIT Scholar in Cancer Research. Conceptualization, P.Y. K.H. J.M. and R.K.; Methodology, P.Y. A.K.D. P.V. J.R-C. and I.W.; Investigation, P.Y. A.K.D. R.K.K. L.S.L, P.V. J.F. B.C.T. S.W. Y.L. B.P.C, C.G. Y.Y. L.N.K. J.R-C. M.H. R.M. T.T. K.I. N.G. and G.R.; Resources, M.H. R.M. T.T. and K.I.; Writing ? Original Draft, P.Y.; Writing ? Review & Editing, P.Y. J.M. and R.K.; Visualization, P.Y. R.K.K. and L.N.K.; Supervision, I.W. J.M. and R.K.; Funding Acquisition, I.W. J.M. and R.K. M.H. R.M. T.T. and K. I. are employees of Daiichi-Sankyo. Compound B and Compound C are patented under patent WO2015125785 by Daiichi-Sankyo. J.D.M. receives licensing royalties from the NCI and UT Southwestern for cell lines. All other authors report no conflicts of interest. Publisher Copyright: {\textcopyright} 2019 Elsevier Ltd",
year = "2020",
month = jan,
day = "16",
doi = "10.1016/j.chembiol.2019.12.005",
language = "English (US)",
volume = "27",
pages = "105--121.e14",
journal = "Cell Chemical Biology",
issn = "2451-9448",
publisher = "Elsevier Inc.",
number = "1",
}