The impressive clinical activity of small-molecule receptor tyrosine kinase inhibitors for oncogene-addicted subgroups of non-small-cell lung cancer (for example, those driven by activating mutations in the gene encoding epidermal growth factor receptor (EGFR) or rearrangements in the genes encoding the receptor tyrosine kinases anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 (ROS1) and rearranged during transfection (RET)) has established an oncogene-centric molecular classification paradigm in this disease. However, recent studies have revealed considerable phenotypic diversity downstream of tumour-initiating oncogenes. Co-occurring genomic alterations, particularly in tumour suppressor genes such as TP53 and LKB1 (also known as STK11), have emerged as core determinants of the molecular and clinical heterogeneity of oncogene-driven lung cancer subgroups through their effects on both tumour cell-intrinsic and non-cell-autonomous cancer hallmarks. In this Review, we discuss the impact of co-mutations on the pathogenesis, biology, microenvironmental interactions and therapeutic vulnerabilities of non-small-cell lung cancer and assess the challenges and opportunities that co-mutations present for personalized anticancer therapy, as well as the expanding field of precision immunotherapy.

中文翻译：

---

非小细胞肺癌生物学和治疗中同时发生的基因组改变。

小分子受体酪氨酸激酶抑制剂对致癌基因成瘾的非小细胞肺癌亚组（例如，由激活编码表皮生长因子受体 (EGFR) 的基因突变或基因重排驱动的那些）令人印象深刻的临床活性编码受体酪氨酸激酶间变性淋巴瘤激酶 (ALK)、ROS 原癌基因 1 (ROS1) 和转染过程中重排 (RET)) 已在该疾病中建立了以癌基因为中心的分子分类范式。然而，最近的研究揭示了肿瘤起始癌基因下游的相当大的表型多样性。共同发生的基因组改变，特别是肿瘤抑制基因，如 TP53 和 LKB1（也称为 STK11），通过它们对肿瘤细胞内在和非细胞自主癌症标志的影响，已成为致癌基因驱动的肺癌亚组分子和临床异质性的核心决定因素。在这篇综述中，我们讨论了共突变对非小细胞肺癌的发病机制、生物学、微环境相互作用和治疗脆弱性的影响，并评估了共突变对个体化抗癌治疗的挑战和机遇，以及精准免疫治疗领域不​​断扩大。