Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Nat Rev Cancer. 2019 Sep;19(9):495-509. doi: 10.1038/s41568-019-0179-8. Epub 2019 Aug 12.
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.
小分子受体酪氨酸激酶抑制剂在非小细胞肺癌（例如，由编码表皮生长因子受体（EGFR）的基因中的激活突变或受体酪氨酸激酶间变性淋巴瘤激酶（ALK）、ROS 原癌基因 1（ROS1）和重排期间转染（RET）的基因中的重排驱动的那些）的癌基因成瘾亚组中的令人印象深刻的临床活性，在这种疾病中确立了一个以癌基因为中心的分子分类范例。然而，最近的研究揭示了起始肿瘤的癌基因下游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），通过其对肿瘤细胞内在和非细胞自主的癌症特征的影响，成为驱动癌基因的肺癌亚组的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以及日益扩大的精准免疫治疗领域带来的挑战和机遇。
