The Evolution and Ecology of Resistance in Cancer Therapy
The Evolution and Ecology of Resistance in Cancer Therapy
复制标题
肿瘤治疗中耐药的进化和生态学
DOI：
10.1101/cshperspect.a040972
复制
发表时间：
2020-11-01
影响因子：
5.4
通讯作者：
Brown, Joel S.
中科院分区：
文献类型：
--
作者：
Gatenby, Robert A.;Brown, Joel S.
尽管在过去的几十年里，新的治疗策略和药物不断出现，但大多数播散性癌症仍然是致命的。癌细胞通过获取人类基因组的大量信息，具有非凡的能力来部署适应性策略，甚至是最有效的治疗方法。我们注意到治疗耐药的临床表现有两个关键步骤。第一种方法被广泛研究，需要必要的分子机制来消除治疗的细胞毒性作用。然而，耐药表型的出现本身并不具有临床意义。也就是说，耐药细胞只有当它们在第二步耐药中成功增殖到足够大的群体中，从而允许肿瘤进展和治疗失败时，才会影响患者的预后。重要的是，抗性表型的增殖绝不是确定的，事实上，取决于复杂的达尔文动力学，由当地环境和竞争种群背景下抗性机制的成本和收益所控制。针对耐药性分子机制的尝试几乎没有取得临床成功，这主要是因为人类基因组的多样性——一种机制的治疗中断只会导致另一种机制的替代。在这里，我们探索进化知情的策略（适应性、双重结合和灭绝疗法），以克服治疗耐药性，寻求理解和利用控制耐药表型增殖的关键进化动力学。总的来说，这种方法已经证明，虽然癌细胞对当前每种治疗的抗性机制的出现是不可避免的，但耐药表型的增殖不是，也可以延迟，甚至可以通过充分了解潜在的生态进化动力学来阻止。
Despite the continuous deployment of new treatment strategies and agents over many decades, most disseminated cancers remain fatal. Cancer cells, through their access to the vast information of the human genome, have a remarkable capacity to deploy adaptive strategies for even the most effective treatments. We note there are two critical steps in the clinical manifestation of treatment resistance. The first, which is widely investigated, requires molecular machinery necessary to eliminate the cytotoxic effect of the treatment. However, the emergence of a resistant phenotype is not in itself clinically significant. That is, resistant cells affect patient outcomes only when they succeed in the second step of resistance by proliferating into a sufficiently large population to allow tumor progression and treatment failure. Importantly, proliferation of the resistant phenotype is by no means certain and, in fact, depends on complex Darwinian dynamics governed by the costs and benefits of the resistance mechanisms in the context of the local environment and competing populations. Attempts to target the molecular machinery of resistance have had little clinical success largely because of the diversity within the human genome-therapeutic interruption of one mechanism simply results in its replacement by an alternative. Here we explore evolutionarily informed strategies (adaptive, double-bind, and extinction therapies) for overcoming treatment resistance that seek to understand and exploit the critical evolutionary dynamics that govern proliferation of the resistant phenotypes. In general, this approach has demonstrated that, while emergence of resistance mechanisms in cancer cells to every current therapy is inevitable, proliferation of the resistant phenotypes is not and can be delayed and even prevented with sufficient understanding of the underlying eco-evolutionary dynamics.