Drug resistance in cancer: Principles of emergence and prevention

Abstract

Although targeted therapy is yielding promising results in the treatment of specific cancers, drug resistance poses a problem. We develop a mathematical framework that can be used to study the principles underlying the emergence and prevention of resistance in cancers treated with targeted small-molecule drugs. We consider a stochastic dynamical system based on measurable parameters, such as the turnover rate of tumor cells and the rate at which resistant mutants are generated. We find that resistance arises mainly before the start of treatment and, for cancers with high turnover rates, combination therapy is less likely to yield an advantage over single-drug therapy. We apply the mathematical framework to chronic myeloid leukemia. Early-stage chronic myeloid leukemia was the first case to be treated successfully with a targeted drug, imatinib (Novartis, Basel). This drug specifically inhibits the BCR-ABL oncogene, which is required for progression. Although drug resistance prevents successful treatment at later stages of the disease, our calculations suggest that, within the model assumptions, a combination of three targeted drugs with different specificities might overcome the problem of resistance.multiple-drug therapy ͉ mutations ͉ stochastic models

Relapse of acute promyelocytic leukemia with PML-RARα mutant subclones independent of proximate all-trans retinoic acid selection pressure

“…If our hypothesis is correct that PMLRARa mutations are not neutral with respect to the acquisition of secondary mutations that provide a competitive subclone advantage, this suggests a different dynamic for predicting the behavior of mutant APL subclones than posited in recent stochastic models based on analyses of BCR-ABL mutations in imatinib-treated CML. 33,34 Additionally, the prototypic ATRA/ PML-RARa targeted therapy model may be relevant to the nascent therapeutic approach of targeting small molecule regulators to transcription factors in a variety of neoplastic diseases. 35 An inference of our findings is that the development of tumor cell resistance to such agents might not be due just to structural changes that affect interaction with the target molecule but might also involve consequential alterations in other properties of these multifunctional proteins.…”

Apoptosis-based dual molecular targeting by INNO-406, a second-generation Bcr-Abl inhibitor, and ABT-737, an inhibitor of antiapoptotic Bcl-2 proteins, against Bcr-Abl-positive leukemia

“…9,10 Indeed, mathematical modeling studies suggest that complete eradication of Bcr-Abl þ leukemic cells may require simultaneous targeting of other vital molecules. 11,12 Here, we have sought to identify additional therapeutic targets by characterizing the molecular mechanism by which the blockade of Bcr-Abl signaling kills Ph þ leukemia cells. Our study reveals that INNO-406-induced cell death is regulated by the interplay of pro-and antiapoptotic Bcl-2 family proteins that share one to four 'Bcl-2 homology domains (BH1, 2, 3 and BH4)'.…”

Six wedges to curing disease

“…The underlying idea is that total population coverage by two or more therapies is greater than any one alone. For example, Komarova and Wodarz [47] parameterized mathematical models to show how the number of drugs and probabilities of resistance to each inform on how many drugs are necessary to successfully treat cancers. Examples of combined approaches also abound in the antimicrobial literature, for example, the use of multiple phage types or combinations of phages and antibiotics against certain pathogenic bacteria ( [48,49], but see [50]).…”