Dual checkpoint blockade for the treatment of KRAS- or BRAF-driven neoplastic disease
Final Report Abstract
Here, we aimed at characterizing the efficacy of cell cycle checkpoint-abrogating small molecule inhibitors in the treatment of RAS-driven cancers. For that purpose, we initially performed a large-scale unbiased drug synergy screen. This screen revealed a number of novel synergistic drug interactions, including interactions between inhibitors of ATR/WEE1, CHK1/CDK1, CHK1/Topoisomerase-2, GSK3/AMPK, FGFR1/HER2, FGFR1/ALK, CHK1/GLUT1, ATR/GLUT1, CHK1/HER2, ALK/CDK1, GLUT1/ALK, Hexokinase/FGFR1, as well as GSK3/PARP1 and GSK3/Topoisomerase-2. When we mapped synergist effects onto cancer-associated genomic aberrations, we found that particularly combined inhibition of GLUT1 and the ATR/CHK1 axis was particularly toxic in KRAS-mutant cells. We verified this observation through extensive re-screening, using distinct small molecule compounds, as well as genetic silencing of GLUT1, ATR and CHK1. These assays verified a robust synergistic interaction between GLUT1 inhibitors and compounds targeting the ATR/CHK1 axis. We further validated this observation in a Kras-driven model of soft tissue sarcoma in vivo. Whereas single agent GLUT1 or ATR inhibition did not induce tumor shrinkage in this model, combined GLUT1/ATR inhibition led to a shrinkage of pre-existing tumors. Altogether, these data revealed that combined inhibition of glucose uptake and the cell cycle checkpoint machinery may be a way forward in the treatment of KRAS-driven tumors. Our initial screen also indicated that KRAS-mutant tumors may be amenable to PARP1 inhibition, when either UBQLN4 was overexpressed or ATM was inactivated in the context of the KRAS mutation. These somewhat unexpected results were also extensively validated, both in vitro and in vivo. Altogether, our initial screening revealed that KRAS-mutant tumors display a context-specific sensitivity to PARP1 inhibitors.
Publications
- Ercc1 Deficiency Promotes Tumorigenesis and Increases Cisplatin Sensitivity in a TP53 Contextspecific Manner. Molecular Cancer Research, 2016 Aug 11
Jokić M, Vlašić I, Rinneburger M, Klümper N, Spiro J, Vogel W, Offermann A, Kümpers C, Fritz C, Schmitt A, Riabinska, Wittersheim M, Michels S, Ozretić L, Florin A, Welcker D, Akyuz MD, Nowak M, Erkel M, Wolf J, Büttner R, Schumacher B, Thomale J, Persigehl T, Maintz D, Perner S, Reinhardt HC
(See online at https://doi.org/10.1158/1541-7786.MCR-16-0094) - ATM deficiency is associated with sensitivity to PARP1 and ATR inhibitors in lung adenocarcinoma, Cancer Research, 2017 Jun 1;77(11):3040-3056
Schmitt A, Knittel G, Welcker D, Yang T-P, George J, Nowak M, Leeser U, Büttner R, Perner S, Peifer M, Reinhardt HC
(See online at https://doi.org/10.1158/0008-5472.CAN-16-3398) - ATM-deficiency generates genomic instability in pancreatic ductal adenocarcinoma and sensitizes toward therapeutic DNA-damage, Cancer Research, 2017 Oct 15;77(20):5576-5590
Perkhofer L, Schmitt A, Romero M, Ihle M, Hampp S, Ruess DA, Hessmann E, Russell R, Lechel A, Azoitei N, Lin Q, Liebau S, Hohwieler M, Bohnenberger H, Lesina M, Alguel H, Gieldon L, Schroeck E, Gaedcke J, Wagner M, Wiessmüller L, Sipos B, Seufferlein T, Reinhardt HC, Frappart PO, Kleger A
(See online at https://doi.org/10.1158/0008-5472.CAN-17-0634) - AATF suppresses apoptosis, promotes proliferation and is critical for KRAS-driven lung cancer, Oncogene, 2018 Jan 11
Welcker D, Jain M, Khurshid S, Jokic M, Höhne M, Schmitt A, Frommolt P, Niessen C, Spiro J, Persigehl T, Wittersheim M, Büttner R, Fanciulli M, Schermer B, Reinhardt HC, Benzing T, Hopker K
(See online at https://doi.org/10.1038/s41388-017-0054-6) - The Cdkn1aSUPER mouse as a novel tool to study p53-mediated tumor suppression. Cell Reports, 2018 Oct 23;25(4):1027-1039.e6
Torgovnick A, Heger JM, Liaki V, Isensee J, Schmitt A, Knittel G, Riabinska A, Beleggia F, Laurien L, Leeser U, Jüngst C, Siedek F, Vogel W, Klümper N, Nolte H, Wittersheim M, Tharun L, Castiglione R, Krüger M, Schauss A, Perner S, Pasparakis M, Büttner R, Persigehl T, Hucho T, Herter-Sprie GS, Schumacher B, Reinhardt HC
(See online at https://doi.org/10.1016/j.celrep.2018.09.079) - Dual inhibition of GLUT1 and the ATR/CHK1 kinase axis displays synergistic cytotoxicity in KRAS-mutant cancer cells. Cancer Res. 2019 Aug 12. pii: canres.3959.2018
Erber J, Steiner JD, Isensee J, Lobbes LA, Toschka A, Beleggia F, Schmitt A, Kaiser RWJ, Siedek F, Persigehl T, Hucho T, Reinhardt HC
(See online at https://doi.org/10.1158/0008-5472.CAN-18-3959) - UBQLN4 represses homologous recombination and is overexpressed in aggressive tumors, Cell, 2019 Jan 24
Jachimowicz RD, Beleggia F, Isensee J, Bhavana VB, Goergens J, Bustos MA, Doll MA, Shenoy A, Checa-Rodriguez C, Wiederstein JL, Baranes-Bachar K, Bartenhagen C, Hertwig F, Teper N, Nishi T, Schmitt A, Distelmaier F, Lüdecke HJ, Albrecht B, Krüger M, Schumacher B, Geiger T, Hoon DSB, Huertas P, Fischer M, Hucho T, Peifer M, Ziv Y, Reinhardt HC, Wieczorek D, Shiloh Y
(See online at https://doi.org/10.1016/j.cell.2018.11.024)
