Kong et al suggest that drug addiction may allow for alternating therapy, but it is hard to imagine how alternating therapy could deal with cancer cells that are both resistant and not addicted. However small this population, it will be expected to predominate over time.

The in vivo validation results presented by Kong et al show, in a mouse model, that melanoma transplants continued to decrease in size upon removal of the addictive drug. One problem with this evidence, however, is that the melanoma cells introduced into the mice were selected for resistance — and from the data it’s apparent that they are addicted. Yet in a particular patient many combinations of relevant phenotypes exist or can be generated, including resistant non-addicted variants, and therefore can be present during each treatment.


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The addicted phenotype they characterize includes, furthermore, a switch from proliferative to invasive properties. This shift to invasiveness might be trivial if all addicted cells die, but surviving cells may be pro-metastatic. An association of decreased proliferation and increased invasiveness with lower MITF levels and melanoma prognosis has been documented.4

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It is also important to recognize that so long as cancer cells persist, the outcomes of chemotherapeutic interventions are not evolutionarily stable. Upon cessation of an addictive chemotherapeutic agent, the outcome is evolutionarily unstable because the death or impairment of resistant cells may lead to a return to drug sensitivity. The patient will benefit from a temporarily suppressed population of cancer cells, but non-addicted cells will then repopulate. Kong et al found, for example, that the lethality in melanoma cell lines associated with removal of the dabrafenib was close to 100%, but the cells that persisted generated many clones of lineages that emerged within 30 days.

The evolutionary instability of the responses to chemotherapy draws attention to the need to use the drug addiction strategy as part of integrated therapeutic management, in which complementary treatment is directed against the residual cells before they can proliferate and evolve back to a more damaging state. In Kong et al’s cell line experiments, when cessation of dabrafenib exposure was timed with administration of dacarbazine, which inhibits MITF, the damaging effect of the addiction to dabrafenib was enhanced. A strategy that incorporates this “double hit” on addicted cells, together with additional targeting of non-addicted cells, should enhance long-term control.

Sequential and joint use of antimicrobials are integrated into strategies for managing antimicrobial resistance. This approach may prove more powerful in cancer treatment: the lack of transmissibility of cancer cells between people truncates the time over which sophisticated, low-cost resistance to chemotherapeutics could evolve.

References

  1. Dooley AJ, Gupta A, Middleton MR. Ongoing response in BRAF V600E-mutant melanoma after cessation of intermittent vemurafenib therapy: a case report. Target Oncol. 2017;12(3):385. doi: 10.1007/s11523-017-0483-8
  2. Seifert H, Fisher R, Martin-Liberal J, et al. Prognostic markers and tumour growth kinetics in melanoma patients progressing on vemurafenib. Melanoma Res. 2016;26(2):138-44. doi: 10.1097/CMR.0000000000000218
  3. Kong X, Kuilman T, Shahrabi A, et al. Cancer drug addiction is relayed by an ERK2-dependent phenotype switch. Nature. 2017;550(7675):270-4. doi: 10.1038/nature24037
  4. Howlin J, Cirenajwis H, Lettiero B, et al. Loss of CITED1, an MITF regulator, drives a phenotype switch in vitro and can predict clinical outcome in primary melanoma tumours. PeerJ. 2015;3:e788. doi: 10.7717/peerj.788