Cancer Drug Addiction: Prospects for Integrated Therapeutic Management

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The drug addiction strategy must be broadened to account for non-addicted cells, sensitive or resistant, that remain after therapy.
The drug addiction strategy must be broadened to account for non-addicted cells, sensitive or resistant, that remain after therapy.

It is now recognized that cancer cells evolve resistance to therapeutic drugs in a way that parallels the evolution of microbial resistance to antimicrobials. This similarity is particularly evident for chemotherapeutic agents, which exert a strong selective pressure against sensitive cancer cells.

Yet the long-term development of chemotherapeutic and antimicrobial resistances differ, as cancer cells are not, as a rule, transmitted interpersonally. The time over which resistance can evolve among cancer cells is, therefore, markedly truncated. This difference suggests that using chemotherapeutics may be sustainable over longer periods of time if the evolution of resistance within each patient can be managed.

One possibility for managing resistance to chemotherapeutics is exploitation of the evolved drug “addiction” among cancer cells, which we define as the dependence of cancer cells on the chemotherapeutic agent to which they are resistant. When addiction develops, removal of the chemotherapeutic agent puts the addicted cancer cells in a compromised state that may result in their death or reduced malignancy.

Application of this strategy to humans has been suggested by case studies of melanoma in which the BRAF signaling pathway was inhibited by vemurafenib: the inhibitory effect appeared to persist after the cessation of therapy.1,2

In a recent study, Kong et al investigated the mechanism of this drug addiction.3 In melanoma cell lines they found that resistance and addiction to dabrafenib, a BRAF inhibitor, involved a change in the BRAF/ERK-2 signaling pathway, which controls cellular proliferation. The addiction was associated with ERK-2 inhibition of microphthalmia-associated transcription factor (MITF), a protein that fosters cellular survival and proliferation. Restoration of MITF activity allowed the cell lines to survive, demonstrating the role of MITF inhibition in the addiction process.

Phenotypic variation of cancer cells is generated during oncogenesis through genetic and epigenetic modifications. An evolutionary perspective emphasizes the need to consider how selection acts on all the cancer cell variants within a particular patient. If a therapy eliminates only some of the cells, other cancer cells may still be present to generate a relapse, though these remaining cells could be sensitive to a chemotherapeutic agent if it was not able to reach all of the cancerous cells — or they could be resistant but not addicted.

The drug addiction strategy must therefore be broadened to account for non-addicted cells, sensitive or resistant, that remain after therapy. Much as selection should favor the development of drug resistant tumor cell lineages, it should also favor lineages that are resistant to addiction.

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