Abstract
Loss-of-function mutations in KEAP1 frequently occur in lung cancer and are associated with poor prognosis and resistance to standard of care treatment, highlighting the need for the development of targeted therapies. We previously showed that KEAP1 mutant tumors consume glutamine to support the metabolic rewiring associated with NRF2-dependent antioxidant production. Here, using preclinical patient-derived xenograft models and antigenic orthotopic lung cancer models, we show that the glutamine antagonist prodrug DRP-104 impairs the growth of KEAP1 mutant tumors. We find that DRP-104 suppresses KEAP1 mutant tumors by inhibiting glutamine-dependent nucleotide synthesis and promoting antitumor T cell responses. Using multimodal single-cell sequencing and ex vivo functional assays, we demonstrate that DRP-104 reverses T cell exhaustion, decreases Tregs, and enhances the function of CD4 and CD8 T cells, culminating in an improved response to anti-PD1 therapy. Our preclinical findings provide compelling evidence that DRP-104, currently in clinical trials, offers a promising therapeutic approach for treating patients with KEAP1 mutant lung cancer.
| Original language | English (US) |
|---|---|
| Article number | eadm9859 |
| Journal | Science Advances |
| Volume | 10 |
| Issue number | 13 |
| DOIs | |
| State | Published - Mar 2024 |
Funding
Acknowledgments: We thank members of the experimental Pathology Research laboratory, which is partially supported by the cancer center Support Grant P30cA016087 at nYU langone\u2019s laura and isaac Perlmutter cancer center. the Akoya vectra Polaris multispectral scanning system was awarded through the shared instrument grant S10 Od021747. Funding: R.P. was supported by the William Rom Fellowship, the Stony Wold-herbert Fund, and nih training grants t32 cA009161 and t32 Ai100853. t.P. is supported by nih grants (R37cA222504 and R01cA227649) and an American cancer Society Research Scholar Grant (RSG-17-200-01\u2013tBe). t.P. received funding from dracen Pharmaceuticals during the conduct of this study. t.P. also received funding from Kymera therapeutics, Bristol Myers Squibb, and Agios Pharmaceuticals not related to the submitted work. Work in S.B.K. laboratory was supported by nih (R01hl-125816 and R01cA271245), leO Foundation Grant (lF-Oc-20-000351), and nYU cancer center Pilot grant (P30cA016087). PdX generation was supported by nih P30 cA008748 and the druckenmiller center for lung cancer Research. the study was partly Acknowledgments: We thank members of the experimental Pathology Research laboratory, which is partially supported by the cancer center Support Grant P30cA016087 at nYU langone\u2019s laura and isaac Perlmutter cancer center. the Akoya vectra Polaris multispectral scanning system was awarded through the shared instrument grant S10 Od021747. Funding: R.P. was supported by the William Rom Fellowship, the Stony Wold-herbert Fund, and nih training grants t32 cA009161 and t32 Ai100853. t.P. is supported by nih grants (R37cA222504 and R01cA227649) and an American cancer Society Research Scholar Grant (RSG-17-200-01\u2013 tBe). t.P. received funding from dracen Pharmaceuticals during the conduct of this study. t.P. also received funding from Kymera therapeutics, Bristol Myers Squibb, and Agios Pharmaceuticals not related to the submitted work. Work in S.B.K. laboratory was supported by nih (R01hl-125816 and R01cA271245), leO Foundation Grant (lF-Oc-20-000351), and nYU cancer center Pilot grant (P30cA016087). PdX generation was supported by nih P30 cA008748 and the druckenmiller center for lung cancer Research. the study was partly supported by dracen Pharmaceuticals inc. Authors contributions: R.P., S.e.l., S.B.K., and t.P. conceived the project, designed the experiments, and wrote the manuscript. R.P., S.e.l., A.R., S.M.h., c.B., W.l.W., B.K.-F., A.h., e.i., M.c., J.P.B., M.h., S.R., v.i.S., and t.K. performed experiments. R.P. and S.e.l. analyzed in vitro and in vivo data. c.n. and J.P.B. analyzed the metabolomics data. Y.h. performed the single-cell analysis. v.i.S., K.M.K., and K.-K.W. provided conceptual advice. R.W. provided conceptual advice and edited the manuscript. A.t. supervised the single-cell analysis. J.t.P. and c.M.R. provided PdX models. S.M.d. supervised the metabolomics experiments/analysis. S.B.K. supervised the immune analysis and single-cell analysis. t.P. supervised the study. All authors reviewed the manuscript. Competing interests: R.W. is a co-founder and holds equity in dracen Pharmaceuticals inc. R.W. has a patent for Pct/ US2020/017748 pending, a patent for Pct/US2020/017750 pending, a patent for WO/2020/150639 pending, and a patent for Pct/US2020/054071 pending related to dRP-104. All intellectual property rights and patents to dRP-104 have been licensed to dracen Pharmaceuticals inc. t.P. has two patents (US-20210361603-A1 and US-20210085763-A1) related to this manuscript that are pending. t.P. is a consultant for vividion therapeutics, tohoku University, and Faeth therapeutics. the authors declare no other competing interests. Data and materials availability: Single-cell data have been deposited in GeO (accession number GSe237592). Otherwise, all data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials.
ASJC Scopus subject areas
- General
