The biggest hurdle to targeted cancer therapy is the inevitable emergence of drug resistance. Tumor cells employ different mechanisms to resist the targeting agent. Most commonly in EGFR-mutant non-small cell lung cancer, secondary resistance mutations on the target kinase domain emerge to diminish the binding affinity of first- and second-generation inhibitors. Other alternative resistance mechanisms include activating complementary bypass pathways and phenotypic transformation. Sequential monotherapies promise to temporarily address the problem of acquired drug resistance, but evidently are limited by the tumor cells' ability to adapt and evolve new resistance mechanisms to persist in the drug environment. Recent studies have nominated a model of drug resistance and tumor progression under targeted therapy as a result of a small subpopulation of cells being able to endure the drug (minimal residual disease cells) and eventually develop further mutations that allow them to regrow and become the dominant population in the therapy-resistant tumor. This subpopulation of cells appears to have developed through a subclonal event, resulting in driver mutations different from the driver mutation that is tumor-initiating in the most common ancestor. As such, an understanding of intratumoral heterogeneity-the driving force behind minimal residual disease-is vital for the identification of resistance drivers that results from branching evolution. Currently available methods allow for a more comprehensive and holistic analysis of tumor heterogeneity in that issues associated with spatial and temporal heterogeneity can now be properly addressed. This review provides some background regarding intratumoral heterogeneity and how it leads to incomplete molecular response to targeted therapies, and proposes the use of single-cell methods, sequential liquid biopsy, and multiregion sequencing to discover the link between intratumoral heterogeneity and early adaptive drug resistance. In summary, minimal residual disease as a result of intratumoral heterogeneity is the earliest form of acquired drug resistance. Emerging technologies such as liquid biopsy and single-cell methods allow for studying targetable drivers of minimal residual disease and contribute to preemptive combinatorial targeting of both drivers of the tumor and its minimal residual disease cells.

中文翻译：

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肺癌靶向治疗中肿瘤异质性和耐药机制的新兴见解。

靶向癌症治疗的最大障碍是不可避免地出现耐药性。肿瘤细胞采用不同的机制来抵抗靶向剂。在EGFR突变的非小细胞肺癌中，最常见的是靶标激酶结构域上的继发性耐药突变出现，从而削弱了第一代和第二代抑制剂的结合亲和力。其他替代抗性机制包括激活互补旁路途径和表型转化。顺序单一疗法有望暂时解决获得性耐药的问题，但显然受到肿瘤细胞适应和发展新的耐药机制以在药物环境中持久存在的能力的限制。最近的研究已指定了靶向治疗下的耐药性和肿瘤进展模型，这是由于能够忍受药物的少量亚群细胞（最小残留疾病细胞）并最终发展出进一步的突变，使它们能够长大并成为优势基因。人群中有抗药性的肿瘤。细胞的这种亚群似乎是通过亚克隆事件发展而来的，其导致的驱动子突变不同于在最常见的祖先中由肿瘤引发的驱动子突变。因此，对肿瘤内异质性（最小残留疾病背后的驱动力）的理解对于鉴定由分支进化产生的抗药性驱动程序至关重要。当前可用的方法允许对肿瘤异质性进行更全面和全面的分析，因为与空间和时间异质性相关的问题现在可以得到适当解决。这篇综述提供了有关肿瘤内异质性及其如何导致对靶向疗法的分子反应不完全的一些背景，并提出了使用单细胞方法，连续液体活检和多区域测序的方法，以发现肿瘤内异质性与早期适应性耐药之间的联系。总之，肿瘤内异质性导致的最小残留疾病是获得性耐药的最早形式。