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STI-571 must select for drug-resistant cells but ‘no cell breathes fire out of its nostrils like a dragon’

Leukemia volume 16, pages 570–572 (2002)Cite this article

Abstract

Seemingly disappointing, the Bcr-Abl kinase inhibitor STI-571 shares an ‘unfortunate’ characteristic with conventional cancer drugs: the development of drug resistance. I argue that the resistance must develop even faster to STI-571 than to conventional drugs, because STI-571 is so effective. This is predictable, but is it inevitable? And how do mechanisms of resistance in relapse depend on a degree of remission. In addition to mutation rate and number of tumor cells, one additional factor determines relapse vs ‘extinction’ of the leukemia cell population.

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References

  1. Druker BJ, Lydon NB . Lessons learned from the development of an Abl tyrosine inhibitor for chronic myelogenous leukemia J Clin Invest 2000 105: 3–7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Laurent E, Talpaz M, Kantarjian H, Kurzrock R . The BCR gene and Philadelphia chromosome-positive leukomogenesis Cancer Res 2001 61: 2343–2355

    CAS  PubMed  Google Scholar 

  3. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL . Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia N Engl J Med 2001 344: 1031–1037

    Article  CAS  PubMed  Google Scholar 

  4. Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, Capdeville R, Talpaz M . Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome N Engl J Med 2001 344: 1038–1042

    Article  CAS  PubMed  Google Scholar 

  5. gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, Sawyers CL . Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification Science 2001 293: 876–880

    Article  CAS  PubMed  Google Scholar 

  6. Marx J . Cancer research. Why some leukemia cells resist STI-571 Science 2001 292: 2231–2233

    Article  CAS  PubMed  Google Scholar 

  7. McCormick F . New-age drug meets resistance Nature 2001 412: 281–282

    Article  CAS  PubMed  Google Scholar 

  8. Blagosklonny MV . How carcinogens (or telomere dysfunction) induce genetic instability: associated-selection model FEBS Lett 2001 506: 169–172

    Article  CAS  PubMed  Google Scholar 

  9. Lengauer C, Kinzler KW, Vogelstein B . Genetic instability in human cancer Nature 1998 396: 643–649

    Article  CAS  PubMed  Google Scholar 

  10. Gambacorti-Passerini C, Barni R, Marchesi E, Verga M, Rossi F, Rossi F, Pioltelli P, Pogliani E, Corneo GM . Sensitivity to the abl inhibitor STI571 in fresh leukaemic cells obtained from chronic myelogenous leukaemia patients in different stages of disease Br J Haematol 2001 112: 972–974

    Article  CAS  PubMed  Google Scholar 

  11. Ohyashiki K, Iwama H, Tauchi T, Shimamoto T, Hayashi S, Ando K, Kawakubo K, Ohyashiki JH . Telomere dynamics and genetic instability in disease progression of chronic myeloid leukemia Leuk Lymphoma 2000 40: 49–56

    Article  CAS  PubMed  Google Scholar 

  12. le Coutre P, Tassi E, Varella-Garcia M, Barni R, Mologni L, Cabrita G, Marchesi E, Supino R, Gambacorti-Passerini C . Induction of resistance to the Abelson inhibitor STI571 in human leukemic cells through gene amplification Blood 2000 95: 1758–1766

    CAS  PubMed  Google Scholar 

  13. Mahon FX, Deininger MW, Schultheis B, Chabrol J, Reiffers J, Goldman JM, Melo JV . Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance Blood 2000 96: 1070–1079

    CAS  PubMed  Google Scholar 

  14. Weisberg E, Griffin JD . Mechanism of resistance to the ABL tyrosine kinase inhibitor STI571 in BCR/ABL-transformed hematopoietic cell lines Blood 2000 95: 3498–3505

    CAS  PubMed  Google Scholar 

  15. Nieborowska-Skorska M, Slupianek A, Skorski T . Progressive changes in the leukemogenic signaling in BCR/ABL-transformed cells Oncogene 2000 19: 4117–4124

    Article  CAS  PubMed  Google Scholar 

  16. Sirulink A, Silver RT, Najfeld V . Marked ploidy and BCR-ABL gene amplification in vivo in a patient treated with STI571 Leukemia 2001 15: 1795–1797

    Article  CAS  PubMed  Google Scholar 

  17. Mohammed M, Shin S, Deng S, Ford J, Paquette RL, Sawyers CL . BCR/ABL gene amplification: a possible mechanism of drug resistance in patients treated with an ABL specific kinase inhibitor Blood 2000 96: Abstr. 1486

  18. Hochhaus A, Kreil S, Corbin A, La Rosee P, Lahaye T, Berger U, Cross NC, Linkesch W, Druker BJ, Hehlmann R, Gambacorti-Passerini C, Corneo G, D'Incalci M, Barthe C, Cony-Makhoul P, Melo JV, Mahon JR, Gorre M, Shah N, Ellwood K, Nicoll J, Sawyers CL . Roots of clinical resistance to STI-571 cancer therapy Science 2001 293: 2163

    Article  CAS  PubMed  Google Scholar 

  19. Issaad C, Ahmed M, Novault S, Bonnet ML, Bennardo T, Varet B, Vainchenker W, Turhan AG . Biological effects induced by variable levels of BCR-ABL protein in the pluripotent hematopoietic cell line UT-7 Leukemia 2000 14: 662–670

    Article  CAS  PubMed  Google Scholar 

  20. Nimmanapalli R, O'Bryan E, Bhalla K . Geldanamycin and its analogue 17-allylamino-17-demethoxygeldanamycin lowers Bcr-Abl levels and induces apoptosis and differentiation of Bcr-Abl-positive human leukemic blasts Cancer Res 2001 61: 1799–1804

    CAS  PubMed  Google Scholar 

  21. Blagosklonny MV, Fojo T, Bhalla KN, Kim J-S, Trepel JB, Figg WD, Rivera Y, Neckers LM . The Hsp90 inhibitor geldanamycin selectively sensitizes Bcr-Abl-expressing leukemia cells to cytotoxic chemotherapy Leukemia 2001 15: 1537–1543

    Article  CAS  PubMed  Google Scholar 

  22. Dawkins R . The Blind Watchmaker W Norton & Co: New York 1986

    Google Scholar 

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  1. MD and Department of Medicine, Medicine Branch, National Cancer Institute, NIH, Bethesda, New York Medical College, Valhalla, NY, USA

    MV Blagosklonny

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Blagosklonny, M. STI-571 must select for drug-resistant cells but ‘no cell breathes fire out of its nostrils like a dragon’. Leukemia 16, 570–572 (2002). https://doi.org/10.1038/sj.leu.2402409

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