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Acute myeloid leukemia

Distinct and overlapping mechanisms of resistance to azacytidine and guadecitabine in acute myeloid leukemia

Leukemia volume 34, pages 3388–3392 (2020)Cite this article

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Cytosine analog hypomethylating agents (HMAs) constitute one of the few approved life-prolonging therapies for myelodysplasia (MDS) and acute myeloid leukemia (AML) in patients who are ineligible for intensive therapy [1]. HMAs are incorporated into DNA during replication and function to covalently ‘trap’ and degrade DNA methyltransferase enzymes (DNMTs) leading to global loss of DNA methylation. The resultant re-expression of silenced tumor suppressor genes and interferon signaling triggered by reactivation of endogenous retroviruses combine to produce potent anti-leukemic effects [2,3,4]. Notwithstanding their efficacy, the development of acquired resistance and treatment failure is universal, even following initial complete remission [5]. While some studies have begun to explore the underlying molecular basis of HMA resistance [6,7,8,9], unbiased genome-wide approaches have not yet been performed.

Clinically utilized HMAs can be broadly classified into two distinct chemotypes—ribonucleosides and deoxyribonucleosides. Although these molecular subtypes have largely been viewed as equivalent therapeutic modalities, multiple lines of evidence both experimental and clinical, hint at overlapping but distinct modes of action and mechanisms of resistance. Whereas deoxyribonucleosides are incorporated into DNA only, ribonucleosides are incorporated into both RNA and DNA and can exert biological effects via interaction with RNA methyltransferases [10]. A direct head-to-head comparison of the ribonucleoside azacitidine (AZA) and the deoxyribonucleoside decitabine (DAC) in AML cell lines revealed differential effects on gene expression, proliferation and cell death [11]. Moreover, in a phase 2 trial of guadecitabine (GDAC; SGI-110), a ‘next-generation’ dinucleotide decitabine analog, a proportion of MDS and AML patients that were primary refractory or relapsed after AZA treatment responded to GDAC [12]. This observation may be explained by differential pharmacological characteristics of GDAC, which is less susceptible than first generation hypomethylators to inactivation by cytidine deaminase. GDAC was subsequently demonstrated to be non-inferior to investigator treatment choice (AZA or DAC in the majority of cases) in treatment-naïve AML patients unfit for intensive chemotherapy induction therapy. Interestingly, GDAC also demonstrated an overall survival benefit over the control arm in subjects receiving at least four or six cycles [13]. These and other observations prompted us to explore and compare AZA and GDAC resistance mechanisms using CRISPR/Cas9 technology.

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Fig. 1: Identification of AZA and GDAC resistance mechanisms in THP1 cells using a genome-wide CRISPR screen.
Fig. 2: Loss of SLC29A1, DCK and UCK2 mediate distinct resistance patterns to AZA, GDAC, and cytarabine.

References

  1. Quintás-Cardama A, Santos FPS, Garcia-Manero G. Therapy with azanucleosides for myelodysplastic syndromes. Oncogene. 2010;7:433–44.

    Google Scholar 

  2. Tsai H-C, Li H, Van Neste L, Cai Y, Robert C, Rassool FV, et al. Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells. Cancer Cell. 2012;21:430–46.

    Article  CAS  Google Scholar 

  3. Chiappinelli KB, Strissel PL, Desrichard A, Li H, Henke C, Akman B, et al. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell. 2015;162:974–86.

    Article  CAS  Google Scholar 

  4. Roulois D, Loo Yau H, Singhania R, Wang Y, Danesh A, Shen SY, et al. DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts. Cell. 2015;162:961–73.

    Article  CAS  Google Scholar 

  5. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009;10:223–32.

    Article  CAS  Google Scholar 

  6. Qin T, Jelinek J, Si J, Shu J, Issa J-PJ. Mechanisms of resistance to 5-aza-2’-deoxycytidine in human cancer cell lines. Blood. 2009;113:659–67.

    Article  CAS  Google Scholar 

  7. Sripayap P, Nagai T, Uesawa M, Kobayashi H, Tsukahara T, Ohmine K, et al. Mechanisms of resistance to azacitidine in human leukemia cell lines. Exp Hematol. 2014;42:294–306.e2.

    Article  CAS  Google Scholar 

  8. Valencia A, Masala E, Rossi A, Martino A, Sanna A, Buchi F, et al. Expression of nucleoside-metabolizing enzymes in myelodysplastic syndromes and modulation of response to azacitidine. Leukemia. 2014;28:621–8.

    Article  CAS  Google Scholar 

  9. Unnikrishnan A, Papaemmanuil E, Beck D, Deshpande NP, Verma A, Kumari A, et al. Integrative genomics identifies the molecular basis of resistance to azacitidine therapy in myelodysplastic syndromes. Cell Rep. 2017;20:572–85.

    Article  CAS  Google Scholar 

  10. Cheng JX, Chen L, Li Y, Cloe A, Yue M, Wei J, et al. RNA cytosine methylation and methyltransferases mediate chromatin organization and 5-azacytidine response and resistance in leukaemia. Nat Commun. 2018;2018:1–16.

    Google Scholar 

  11. Hollenbach PW, Nguyen AN, Brady H, Williams M, Ning Y, Richard N, et al. a comparison of azacitidine and decitabine activities in acute myeloid leukemia cell lines. PLoS ONE. 2010;5:e9001.

    Article  Google Scholar 

  12. Sebert M, Renneville A, Bally C, Peterlin P, Beyne-Rauzy O, Legros L, et al. A phase II study of guadecitabine in higher-risk myelodysplastic syndrome and low blast count acute myeloid leukemia after azacitidine failure. Haematologica. 2019;104:1565–71.

    Article  CAS  Google Scholar 

  13. Roboz GJ, Döhner H, Gobbi M, Kropf PL, Mayer J, Krauter J, et al. Results from a global randomized phase 3 study of guadecitabine (G) vs treatment choice (TC) in 815 patients with treatment naïve (TN) AML unfit for intensive chemotherapy (IC) ASTRAL-1 study: analysis by Number of cycles. Blood. 2019;134:2591–1.

    Article  Google Scholar 

  14. Issa JPJ, Roboz G, Rizzieri D, Jabbour E, Stock W, O’Connell C, et al. Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study. Lancet Oncol. 2015;16:1099–110.

    Article  CAS  Google Scholar 

  15. Gu X, Tohme R, Tomlinson B, Hasipek M, Durkin L, Schuerger C, et al. Resistance to decitabine and 5-azacytidine emerges from adaptive responses of the pyrimidine metabolism network. bioRxiv 2020.02.20.958405; https://doi.org/10.1101/2020.02.20.958405.

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Acknowledgements

This work was supported by a grant in aid from the Cancer Council of Victoria to JS and LMK. LMK was supported by a fellowship from the Victorian Cancer Agency, JS was supported by a fellowship from the Australian Medical Research Future Fund, RWJ was supported by a fellowship from the National Health and Medical Research Council of Australia and EG was supported by the Australian Postgraduate Award.

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  1. The Peter MacCallum Cancer Centre, Melbourne, 3000, VIC, Australia

    Emily Gruber, Rheana L. Franich, Jake Shortt, Ricky W. Johnstone & Lev M. Kats

  2. The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, 3052, VIC, Australia

    Emily Gruber, Ricky W. Johnstone & Lev M. Kats

  3. Monash Haematology, Monash Health, Clayton, 3168, VIC, Australia

    Jake Shortt

  4. School of Clinical Sciences at Monash Health, Monash University, Clayton, 3168, VIC, Australia

    Jake Shortt

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Correspondence to Lev M. Kats.

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The laboratory of JS has received research funding from Astex Pharmaceuticals. JS, LMK and RWJ served on the scientific advisory board of Celgene Corp.

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Gruber, E., Franich, R.L., Shortt, J. et al. Distinct and overlapping mechanisms of resistance to azacytidine and guadecitabine in acute myeloid leukemia. Leukemia 34, 3388–3392 (2020). https://doi.org/10.1038/s41375-020-0973-z

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