Maltas Jeff, Tadele Dagim Shiferaw, Durmaz Arda, McFarland Christopher D, Hinczewski Michael, Scott Jacob G
Cleveland Clinic, Translational Hematology Oncology Research, Cleveland, OH.
Case Western Reserve University, School of Medicine, Cleveland, OH.
bioRxiv. 2024 Mar 11:2023.03.16.533001. doi: 10.1101/2023.03.16.533001.
The evolution of resistance remains one of the primary challenges for modern medicine from infectious diseases to cancers. Many of these resistance-conferring mutations often carry a substantial fitness cost in the absence of treatment. As a result, we would expect these mutants to undergo purifying selection and be rapidly driven to extinction. Nevertheless, pre-existing resistance is frequently observed from drug-resistant malaria to targeted cancer therapies in non-small cell lung cancer (NSCLC) and melanoma. Solutions to this apparent paradox have taken several forms from spatial rescue to simple mutation supply arguments. Recently, in an evolved resistant NSCLC cell line, we found that frequency-dependent ecological interactions between ancestor and resistant mutant ameliorate the cost of resistance in the absence of treatment. Here, we hypothesize that frequency-dependent ecological interactions in general play a major role in the prevalence of pre-existing resistance. We combine numerical simulations with robust analytical approximations to provide a rigorous mathematical framework for studying the effects of frequency-dependent ecological interactions on the evolutionary dynamics of pre-existing resistance. First, we find that ecological interactions significantly expand the parameter regime under which we expect to observe pre-existing resistance. Next, even when positive ecological interactions between mutants and ancestors are rare, these resistant clones provide the primary mode of evolved resistance because even weak positive interaction leads to significantly longer extinction times. We then find that even in the case where mutation supply alone is sufficient to predict pre-existing resistance, frequency-dependent ecological forces still contribute a strong evolutionary pressure that selects for increasingly positive ecological effects (negative frequency-dependent selection). Finally, we genetically engineer several of the most common clinically observed resistance mechanisms to targeted therapies in NSCLC, a treatment notorious for pre-existing resistance. We find that each engineered mutant displays a positive ecological interaction with their ancestor. As a whole, these results suggest that frequency-dependent ecological effects can play a crucial role in shaping the evolutionary dynamics of pre-existing resistance.
从传染病到癌症，耐药性的演变仍然是现代医学面临的主要挑战之一。许多赋予耐药性的突变在未接受治疗的情况下往往会带来巨大的适应性代价。因此，我们预计这些突变体会经历净化选择并迅速灭绝。然而，从耐药性疟疾到非小细胞肺癌（NSCLC）和黑色素瘤的靶向癌症治疗，经常会观察到预先存在的耐药性。针对这一明显矛盾的解决方案有多种形式，从空间拯救到简单的突变供应论点。最近，在一个进化出耐药性的NSCLC细胞系中，我们发现祖先细胞和耐药突变体之间频率依赖性的生态相互作用在未接受治疗的情况下减轻了耐药性的代价。在此，我们假设频率依赖性的生态相互作用总体上在预先存在的耐药性的流行中起主要作用。我们将数值模拟与稳健的解析近似相结合，以提供一个严格的数学框架，用于研究频率依赖性生态相互作用对预先存在的耐药性进化动态的影响。首先，我们发现生态相互作用显著扩展了我们预期观察到预先存在的耐药性的参数范围。其次，即使突变体和祖先之间的正向生态相互作用很少见，这些耐药克隆也提供了进化出的耐药性的主要模式，因为即使是微弱的正向相互作用也会导致显著更长的灭绝时间。然后我们发现，即使在仅突变供应就足以预测预先存在的耐药性的情况下，频率依赖性的生态力量仍然会产生强大的进化压力，选择越来越正向的生态效应（负频率依赖性选择）。最后，我们对NSCLC中几种临床上最常见观察到的针对靶向治疗的耐药机制进行基因工程改造，NSCLC的这种治疗因预先存在的耐药性而臭名昭著。我们发现每个工程突变体都与其祖先表现出正向生态相互作用。总体而言，这些结果表明频率依赖性的生态效应在塑造预先存在的耐药性的进化动态中可能起着关键作用。
