TY - JOUR
T1 - Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy
AU - Skoulidis, Ferdinandos
AU - Heymach, John V.
N1 - Funding Information:
The authors acknowledge support from a Department of Defense Lung Cancer Research Program Career Development Award (W81XWH-16-1-0094 to F.S.), a RP160652 Cancer Prevention Research Institute of Texas Multi-Investigator Research Award (to J.V.H.), a NIH/NCI 1R01 CA205150 grant (to J.V.H.), Lung SPORE grant 5 P50 CA070907 and a Stand Up To Cancer–American Cancer Society Lung Cancer Dream Team Translational Research Grant (grant no. SU2C-AACR-DT17-15). Stand Up To Cancer is a programme of the Entertainment Industry Foundation and research grants are administered by the American Association for Cancer Research, the scientific partner of Stand Up To Cancer. In addition, the authors acknowledge generous philanthropic contributions to the University of Texas MD Anderson Lung Cancer Moonshots Program.
Publisher Copyright:
© 2019, Springer Nature Limited.
PY - 2019/9/1
Y1 - 2019/9/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41568-019-0179-8
DO - 10.1038/s41568-019-0179-8
M3 - Review article
C2 - 31406302
AN - SCOPUS:85070827546
SN - 1474-175X
VL - 19
SP - 495
EP - 509
JO - Nature Reviews Cancer
JF - Nature Reviews Cancer
IS - 9
ER -