The Genetic/Non-genetic Duality of Drug 'Resistance' in Cancer

Abstract

Drug resistance is a serious impediment to the treatment of cancer. However, the mechanisms involved remain poorly understood. While it is widely held that the phenomenon is genetic in nature, emerging evidence suggests that non-genetic mechanisms may also be important. Furthermore, at least in some cases, refractoriness to treatment can be reversed by epigenetic reprogramming, and combination and intermittent therapies, as opposed to sustained monotherapy, appear more effective in attenuating it. Here we iterate the confusion in understanding the phenomenon by which cancer cells evade drug response and underscore the need to recognize the genetic/non-genetic duality of drug resistance in cancer. We discuss how ecological and evolutionary principles may help to reconcile the duality and may even offer new treatment strategies.

Keywords: cancer; drug resistance; duality; epigenetic mechanism; intermittent therapy.

Fig. 1. Both genetic and non-genetic mechanisms may underlie phenotypic switching

A) The normal fruit fly (left) has one pair of wings on thoracic segment 2 and a pair of halteres on thoracic segment 3. Edward Lewis discovered the ubx phenotype (right) in which the halteres are transformed into an extra pair of wings (reproduced with permission from the Achieves, California Institute of Technology). The mechanism involved mutations in the regulatory region of the Ubx gene. Conrad Waddington on the other hand also discovered the same phenotype but by exposing fly larvae to ether vapour that is not known to cause mutations. B) A cancer cell that is sensitive to a drug (left) can develop resistance via (right) a genetic mechanism that involves mutations (e.g., BRAF) and is transgenerationally heritable. In contrast it can also develop resistance via non-genetic mechanisms by rewiring the regulatory network (35) and such changes can be transferred to the DNA via epigenetic mechanisms. Thus, the process can be reversed and cancer cells can switch from one phenotype to the other.

Fig. 2. Phenotypic switching and drug resistance in cancer

A) As envisaged by Waddington in his famous epigenetic landscape analogy (40), a phenotype is canalized and buffered against minor fluctuations such that the majority of the individuals in the population exhibit a similar phenotype (phenotype A). Selection pressure acts as a threshold (red vertical bar). B) In response to changes in the environment (e.g., drug treatment), if the threshold is lowered (green vertical bar), then the individuals in the population breach the new threshold and a majority will exhibit the new phenotype (phenotype B).

Fig. 3. Continuous monotherapy versus intermittent combination therapy

A) In continuous monotherapy, the idea is to eradicate the tumor as quickly as possible. However this strategy can give rise resistance and resistant cells are expected to propagate over time (top). In contrast, combination therapy applied intermittently (bottom) could to induce ‘adaptive strategies’ to change the tumor environment in such a way that proliferation of resistant clones can be suppressed for prolonged periods of time. Therapy is applied in small doses to reduce the tumor population only sufficiently to improve symptoms. Furthermore, treatment is intermittent so that drug-sensitive cells will proliferate at the expense of the resistant ones. B & C). Although the tumor will increase in size between treatments, the extant tumor cells will continue to be sensitive to therapy. Modified from (30).