Evolution of Resistance During Clonal Expansion

Acquired drug resistance is a major limitation for cancer therapy. Often, one genetic alteration suffices to confer resistance to an otherwise successful therapy. However, little is known about the dynamics of the emergence of resistant tumor cells. In this article, we consider an exponentially grow...

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Veröffentlicht in:Genetics (Austin) 2006-04, Vol.172 (4), p.2557-2566
Hauptverfasser: Iwasa, Yoh, Nowak, Martin A, Michor, Franziska
Format: Artikel
Sprache:eng
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Zusammenfassung:Acquired drug resistance is a major limitation for cancer therapy. Often, one genetic alteration suffices to confer resistance to an otherwise successful therapy. However, little is known about the dynamics of the emergence of resistant tumor cells. In this article, we consider an exponentially growing population starting from one cancer cell that is sensitive to therapy. Sensitive cancer cells can mutate into resistant ones, which have relative fitness alpha prior to therapy. In the special case of no cell death, our model converges to the one investigated by Luria and Delbrück. We calculate the probability of resistance and the mean number of resistant cells once the cancer has reached detection size M. The probability of resistance is an increasing function of the detection size M times the mutation rate u. If Mu 1, to l nM for neutral mutants (alpha = 1), but converges to an upper limit for deleterious mutants (alpha
ISSN:0016-6731
1943-2631
1943-2631
DOI:10.1534/genetics.105.049791