A growing trend in medicine, especially with regard to medical oncology, is targeted therapy, which is often combined with other cancer treatments in patients with advanced disease [1–۳]. While patients respond fairly well initially, in most cancers sustained treatment typically results in the failure of response to treatment (typically referred to as drug resistance) with a poorer prognosis. Furthermore, challenges and complexities regarding toxicity when combining these therapies and how to personalize medicine – selecting the right patient population that can benefit from therapies and not develop drug resistance – remain a concern.

Understanding How Cancer Cells Become Refractory to Drug Treatment

Although today we have a much greater understanding of cancer biology and genetics, one of the main reasons for our failure to overcome so-called drug resistance in cancer may relate to the difficulty of how we perceive the phenomenon (see Box 1 for the various mechanisms by which organisms can evade drug treatment; for the sake of simplicity here, we refer to it as drug resistance). Is the phenomenon driven solely by genetic mechanisms (i.e., is it irreversible and deterministic)? Alternatively, are other, non-genetic mechanisms, such as stochastic phenotypic switching or epigenetic factors that promote intrinsic diversity and phenotypic plasticity, involved? If so, can this information help in guiding treatment decisions that are currently based solely on genetic biomarkers? Unfortunately, it appears that the phenomenon is much more nuanced [4]. The water is muddied further by seemingly conflicting reports in the literature ([5] see also the examples discussed below) and the erroneous assumption that drug resistance, tolerance, and persistence are synonymous or equivalent, albeit inadvertently (Box 1). Here we consider two recent studies as a case in point; while one emphasizes the genetic underpinning of drug resistance, the other points to a non-genetic mechanism in the same cancer type. Using these two cases as recent examples, we stress the need to recognize the genetic/non-genetic duality of drug resistance in cancer and discuss how ecological and evolutionary principles may help to reconcile the duality and may even offer new strategies for treatment and prevention o drug resistance. However, the reader is referred to several excellent reviews for an in-depth discussion [6–۸] and recent reports underscoring non-genetic mechanisms underlying drug resistance in cancer [9].