Wahl, Daniel
Mayo Clinic
Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.
Citations 2
GTP Signaling Links Metabolism, DNA Repair, and Responses to Genotoxic Stress
Zhou, Weihua , Zhao, Zitong , Lin, Angelica , Yang, John Z. , Xu, Jie , Wilder-Romans, Kari , Yang, Annabel , Li, Jing , Solanki, Sumeet , Speth, Jennifer M. , Scott, Andrew J. , Wang, L. , Wen, Bo , Andren, Anthony , Zhang, Li , Yao, Yangyang , Peterson, Erik , Korimerla, Navyateja , Werner, Christian K. , Ullrich, Alexander , Liang, Jessica , Jacobson, Janna , O’Brien, Alexandra M., Elaimy, Ameer L. , Ferris, Sean P. , Zhao, Shuang G. , Zhang, Shuqun , Al‐Holou, Wajd N. , Umemura, Yoshie , Morgan, Meredith A. , Lawrence, Theodore S. , Lyssiotis, Costas A. , Peters‐Golden, Marc , Wahl, Daniel , Walker, Natalie , Scott, Andrew J , Wang, Lu , Wen, Bo , Andren, Anthony , Zhang, Li , Kothari, Ayesha U , Yao, Yangyang , Peterson, Erik , Korimerla, Navyateja , Werner, Christian K , Ullrich, Alexander , Liang, Jessica , Jacobson, Janna , Palavalasa, Sravya , O'Brien, Alexandra M , Elaimy, Ameer L , Ferris, Sean P , Zhao, Shuang G , Sarkaria, Jann N , Győrffy, Balázs , Zhang, Shuqun , Al-Holou, Wajd N , Umemura, Yoshie , Morgan, Meredith A , Lawrence, Theodore S , Lyssiotis, Costas A , Peters-Golden, Marc , Shah, Yatrik M , Wahl, Daniel , Kothari, Ayesha U. , Sarkaria, Jann N. , Győrffy, Balázs
Cancer Discovery | October 30, 2023 | Volume: 14 | Issue: 1 | Pages: 158-175
ABSTRACT How cell metabolism regulates DNA repair is incompletely understood. Here, we define a GTP-mediated signaling cascade that links metabolism to DNA repair and has significant therapeutic implications. GTP, but not other nucleotides, regulates the activity of Rac1, a guanine nucleotide-binding protein, which promotes the dephosphorylation of serine 323 on Abl-interactor 1 (Abi-1) by protein phosphatase 5 (PP5). Dephosphorylated Abi-1, a protein previously not known to activate DNA repair, promotes nonhomologous end joining. In patients and mouse models of glioblastoma, Rac1 and dephosphorylated Abi-1 mediate DNA repair and resistance to standard-of-care genotoxic treatments. The GTP–Rac1–PP5–Abi-1 signaling axis is not limited to brain cancer, as GTP supplementation promotes DNA repair and Abi-1-S323 dephosphorylation in nonmalignant cells and protects mouse tissues from genotoxic insult. This unexpected ability of GTP to regulate DNA repair independently of deoxynucleotide pools has important implications for normal physiology and cancer treatment. SIGNIFICANCE: A newly described GTP-dependent signaling axis is an unexpected link between nucleotide metabolism and DNA repair. Disrupting this pathway can overcome cancer resistance to genotoxic therapy while augmenting it can mitigate genotoxic injury of normal tissues. This article is featured in Selected Articles from This Issue, p. 5
Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways
Venneti, Sriram , Kawakibi, Abed Rahman , Ji, Sunjong , Waszak, Sebastian M. , Sweha, Stefan R. , Mota, Mateus , Pun, Matthew , Deogharkar, Akash , Chung, Chan , Tarapore, Rohinton S. , Ramage, Samuel , Chi, Andrew , Wen, Patrick Y. , Arrillaga‐Romany, Isabel , Batchelor, Tracy T. , Butowski, Nicholas , Shonka, Nicole , Hall, Matthew D. , Daghistani, Doured , Beccaria, Kévin , Umemura, Yoshie , Garton, Hugh , Franson, Andrea , Schwartz, Jonathan , Kachman, Maureen , Baum, Heidi , Burant, Charles , Mottl, Sophie L. , Cartaxo, Rodrigo T. , John, Vishal , Messinger, Dana , Peterson, Erik , Ravi, Karthik , Waugh, Alyssa , Walling, Dustin , Ding, Yujie , Xia, Ziyun , Hawes, Debra , Yang, Fusheng , Judkins, Alexander R. , Wahl, Daniel , Lyssiotis, Costas A. , Nava, Daniel de la , Eze, Augustine , Spitzer, Jasper , Schmidt, Susanne V. , Cain, Jason E. , Jiang, Li , Agar, Nathalie Y.R. , Zhao, Lili , Mody, Rajen , Kurokawa, Ryo , Yadav, Viveka Nand , Grill, Jacques , Kline, Cassie , Mueller, Sabine , Nazarian, Javad , Allen, Joshua E. , Odia, Yazmín , Butowski, Nicholas A , Sumrall, Ashley , Shonka, Nicole , Harrison, Rebecca A , de Groot, John , Mehta, Minesh P , Hall, Matthew D , Daghistani, Doured , Cloughesy, Timothy F , Ellingson, Benjamin M , Beccaria, Kevin , Varlet, Pascale , Kim, Michelle M , Umemura, Yoshie , Garton, Hugh , Franson, Andrea , Schwartz, Jonathan , Jain, Rajan , Kachman, Maureen , Baum, Heidi , Burant, Charles F , Mottl, Sophie L , Cartaxo, Rodrigo T , John, Vishal , Messinger, Dana , Qin, Tingting , Peterson, Erik , Sajjakulnukit, Peter , Ravi, Karthik , Waugh, Alyssa , Walling, Dustin , Ding, Yujie , Xia, Ziyun , Schwendeman, Anna , Hawes, Debra , Yang, Fusheng , Judkins, Alexander R , Wahl, Daniel , Lyssiotis, Costas A , de la Nava, Daniel , Alonso, Marta M , Eze, Augustine , Spitzer, Jasper , Schmidt, Susanne V , Duchatel, Ryan J , Dun, Matthew D , Cain, Jason E , Jiang, Li , Stopka, Sylwia A , Baquer, Gerard , Regan, Michael S , Filbin, Mariella G , Agar, Nathalie Y R , Zhao, Lili , Kumar-Sinha, Chandan , Mody, Rajen , Chinnaiyan, Arul , Kurokawa, Ryo , Pratt, Drew , Yadav, Viveka N , Grill, Jacques , Kline, Cassie , Mueller, Sabine , Resnick, Adam , Nazarian, Javad , Allen, Joshua E , Odia, Yazmin , Gardner, Sharon L , Koschmann, Carl , Tarapore, Rohinton S , Ji, Sunjong , Wen, Patrick Yung , Arrillaga‐Romany, Isabel , Sumrall, Ashley , Groot, John de , Mehta, Minesh P. , Cloughesy, Timothy F. , Ellingson, Benjamin M. , Kim, Michelle M. , Jain, Rajan , Stopka, Sylwia A. , Baquer, Gerard , Regan, Michael S. , Koschmann, Carl
Cancer Discovery | August 16, 2023 | Volume: 13 | Issue: 11 | Pages: 2370-2393
Abstract Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multisite clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle–related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction. Significance: The clinical, radiographic, and molecular analyses included in this study demonstrate the efficacy of ONC201 in H3K27M-mutant DMG and support ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction. This article is featured in Selected Articles from This Issue, p. 2293