Evolutionary dynamics of cancer in response to targeted combination therapy

Ivana Bozic, Johannes G. Reiter, Benjamin Allen, Tibor Antal, Krishnendu Chatterjee, Preya Shah, Yo Sup Moon, Amin Yaqubie, Nicole Kelly, Dung T. Le, Evan J. Lipson, Paul B. Chapman, Luis A. Diaz, Bert Vogelstein, Martin A. Nowak

Research output: Contribution to journalArticlepeer-review

Abstract

In solid tumors, targeted treatments can lead to dramatic regressions, but responses are often short-lived because resistant cancer cells arise. The major strategy proposed for overcoming resistance is combination therapy. We present a mathematical model describing the evolutionary dynamics of lesions in response to treatment. We first studied 20 melanoma patients receiving vemurafenib. We then applied our model to an independent set of pancreatic, colorectal, and melanoma cancer patients with metastatic disease. We find that dual therapy results in long-term disease control for most patients, if there are no single mutations that cause cross-resistance to both drugs; in patients with large disease burden, triple therapy is needed. We also find that simultaneous therapy with two drugs is much more effective than sequential therapy. Our results provide realistic expectations for the efficacy of new drug combinations and inform the design of trials for new cancer therapeutics.

Original languageEnglish (US)
Article numbere00747
JournaleLife
Volume2013
Issue number2
DOIs
StatePublished - Jun 25 2013

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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