Abstract
This chapter discusses the basic evolutionary dynamics of cells that are resistant to small molecule inhibitors in the context of an exponentially growing population of cells, as typically observed in the treatment of CML blast crisis. The basic principles of resistance emergence is discussed. Mathematical models clearly indicate that the pre-treatment tumor growth phase is crucial for the generation of resistant mutants, and that the treatment phase itself does not significantly contribute to the generation of resistant mutants. In this respect, the growth kinetics of the tumor plays an important role. Tumors characterized by a higher turnover of cells have a higher probability to harbor resistant cells at any given tumor size, compared to low-turnover tumors. These insights are then applied to calculate the probability that a tumor of a given size is simultaneously resistant to a number of \(m\) drugs that can be given in combination, based on the parameters of the system. These calculations suggest that in the absence of cross-resistance, a combination of three drugs can prevent resistance-induced treatment failure in CML blast crisis.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Fojo, T., Bates, S.: Strategies for reversing drug resistance. Oncogene 22(47), 7512–23 (2003)
Gottesman, M.: Mechanisms of cancer drug resistance. Annu. Rev. Med. 53(1), 615–627 (2002)
Luqmani, Y.: Mechanisms of drug resistance in cancer chemotherapy. Med. Princ. Pract. 14(1), 35–48 (2005)
Redmond, K., Wilson, T., Johnston, P., Longley, D.: Resistance mechanisms to cancer chemotherapy. Front Biosci. 13, 5138–5154 (2008)
Ozben, T.: Mechanisms and strategies to overcome multiple drug resistance in cancer. FEBS Lett. 580(12), 2903–2909 (2006)
Longley, D., Johnston, P.: Molecular mechanisms of drug resistance. J. Pathol. 205(2), 275–292 (2005)
Druker, B.J.: Imatinib as a paradigm of targeted therapies. Adv. Cancer Res. 91, 1–30 (2004)
Blagosklonny, M.V.: Sti-571 must select for drug-resistant cells but ’no cell breathes fire out of its nostrils like a dragon’. Leukemia 16(4), 570–572 (2002)
Shannon, K.M.: Resistance in the land of molecular cancer therapeutics. Cancer Cell 2(2), 99–102 (2002)
Khorashad, J., Kelley, T., Szankasi, P., Mason, C., Soverini, S., Adrian, L., Eide, C., Zabriskie, M., Lange, T., Estrada, J., et al.: Bcr-abl1 compound mutations in tyrosine kinase inhibitor resistant cml: frequency and clonal relationships. J. Am. Soc. Hematol. 119(10), 2234–2238 (2012)
Simon, V., Ho, D.D.: Hiv-1 dynamics in vivo: implications for therapy. Nat. Rev. Microbiol. 1(3), 181–190 (2003)
Schabel, F.M. Jr., Skipper, H.E., Trader, M.W., Laster, W.R. Jr., Griswold, D.P. Jr., Corbett, T.H.: Establishment of cross-resistance profiles for new agents. Cancer Treat. Rep. 67(10), 905–922 (1983)
Schabel, F.M. Jr., Trader, M.W., Laster, W.R. Jr., Corbett, T.H., Griswold, D.P. Jr.: cis-dichlorodiammineplatinum(ii): combination chemotherapy and cross-resistance studies with tumors of mice. Cancer Treat. Rep. 63(9–10), 1459–1473 (1979)
Coldman, A.J., Goldie, J.H.: A stochastic model for the origin and treatment of tumors containing drug-resistant cells. Bull. Math. Biol. 48(3–4), 279–292 (1986)
McKinnell, R.G., Parchment, R.E., Perantoni, A.O., Pierce, G.B.: The Biological Basis of Cancer. Cambridge University Press, Cambridge (1998)
Calabretta, B., Perrotti, D.: The biology of cml blast crisis. Blood 103(11), 4010–4022 (2004)
McCormick, F.: New-age drug meets resistance. Nature 412(6844), 281–282 (2001)
Gambacorti-Passerini, C.B., Gunby, R.H., Piazza, R., Galietta, A., Rostagno, R., Scapozza, L.: Molecular mechanisms of resistance to imatinib in philadelphia-chromosome-positive leukaemias. Lancet Oncol. 4(2), 75–85 (2003)
Gorre, M.E., Mohammed, M., Ellwood, K., Hsu, N., Paquette, R., Rao, P.N., Sawyers, C.L.: Clinical resistance to sti-571 cancer therapy caused by bcr-abl gene mutation or amplification. Science 293(5531), 876–880 (2001)
Loeb, L.A.: Cancer cells exhibit a mutator phenotype. Adv. Cancer Res. 72, 25–56 (1998)
Tlsty, T.D., Margolin, B.H., Lum, K.: Differences in the rates of gene amplification in nontumorigenic and tumorigenic cell lines as measured by luria-delbruck fluctuation analysis. Proc. Natl. Acad. Sci. U.S.A. 86(23), 9441–9445 (1989)
Loeb, L.A., Springgate, C.F., Battula, N.: Errors in dna replication as a basis of malignant changes. Cancer Res. 34(9), 2311–2321 (1974)
Tipping, A.J., Mahon, F.X., Lagarde, V., Goldman, J.M., Melo, J.V.: Restoration of sensitivity to sti571 in sti571-resistant chronic myeloid leukemia cells. Blood 98(13), 3864–3867 (2001)
Nowicki, M.O., Falinski, R., Koptyra, M., Slupianek, A., Stoklosa, T., Gloc, E., Nieborowska-Skorska, M., Blasiak, J., Skorski, T.: Bcr/abl oncogenic kinase promotes unfaithful repair of the reactive oxygen species-dependent dna double-strand breaks. Blood 104(12), 3746–3753 (2004)
Yoshida, C., Melo, J.V.: Biology of chronic myeloid leukemia and possible therapeutic approaches to imatinib-resistant disease. Int. J. Hematol. 79(5), 420–433 (2004)
Shah, N.P., Tran, C., Lee, F.Y., Chen, P., Norris, D., Sawyers, C.L.: Overriding imatinib resistance with a novel abl kinase inhibitor. Science 305(5682), 399–401 (2004)
Faderl, S., Talpaz, M., Estrov, Z., Kantarjian, H.M.: Chronic myelogenous leukemia: biology and therapy. Ann. Intern. Med. 131(3), 207–219 (1999)
O’Dwyer, M.E., Mauro, M.J., Druker, B.J.: Recent advancements in the treatment of chronic myelogenous leukemia. Annu. Rev. Med. 53, 369–381 (2002)
Al-Hajj, M., Clarke, M.F.: Self-renewal and solid tumor stem cells. Oncogene 23(43), 7274–7282 (2004)
Asquith, B., Debacq, C., Macallan, D.C., Willems, L., Bangham, C.R.: Lymphocyte kinetics: the interpretation of labelling data. Trends Immunol. 23(12), 596–601 (2002)
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
Copyright information
© 2014 Springer Science+Business Media New York
About this chapter
Cite this chapter
Komarova, N.L., Wodarz, D. (2014). Evolutionary Dynamics of Drug Resistant Mutants in Targeted Treatment of CML. In: Targeted Cancer Treatment in Silico. Modeling and Simulation in Science, Engineering and Technology. Birkhäuser, New York, NY. https://doi.org/10.1007/978-1-4614-8301-4_5
Download citation
DOI: https://doi.org/10.1007/978-1-4614-8301-4_5
Published:
Publisher Name: Birkhäuser, New York, NY
Print ISBN: 978-1-4614-8300-7
Online ISBN: 978-1-4614-8301-4
eBook Packages: Mathematics and StatisticsMathematics and Statistics (R0)