Clinical and Translational Implications of RET Rearrangements in Non–Small Cell Lung Cancer Roberto Ferrara, MD, Nathalie Auger, MD, Edouard Auclin,

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Clinical and Translational Implications of RET Rearrangements in Non–Small Cell Lung Cancer Roberto Ferrara, MD, Nathalie Auger, MD, Edouard Auclin, MD, Benjamin Besse, MD, PhD Journal of Thoracic Oncology Volume 13, Issue 1, Pages 27-45 (January 2018) DOI: 10.1016/j.jtho.2017.10.021 Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

Figure 1 Rearranged during transfection proto-oncogene gene (RET) receptor (A) and KIF5B-RET fusion protein (B) activations, with associated triggered downstream pathways. TM, transmembrane domain; E, exon; TK, tyrosine kinase; GFLs, GDNF family of ligands; GFRα, GDNF family receptor α; PI3K, phosphoinositide 3-kinase; MAPK, mitogen-activated protein kinase; JAK, Janus kinase; STAT, signal transducer and activator of transcription; KIF5B, kinesin family member 5B. (Modified with permission from Gainor and Shaw.30) Journal of Thoracic Oncology 2018 13, 27-45DOI: (10.1016/j.jtho.2017.10.021) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

Figure 2 The most frequent rearranged during transfection proto-oncogene gene (RET) rearrangements: kinesin family member 5B gene (KIF5B)-RET (seven variants), coiled-coil domain containing 6 (CCDC6)-RET, nuclear receptor coactivator 4 (NCOA4)-RET, and tripartite motif containing 33 (TRIM33)-RET. E, exon; TM, transmembrane domain. (Modified with permission from Gainor and Shaw.30) Journal of Thoracic Oncology 2018 13, 27-45DOI: (10.1016/j.jtho.2017.10.021) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

Figure 3 Pericentric inversion chromosome 10 (kinesin family member 5B gene [KIF5B]– rearranged during transfection proto-oncogene gene [RET]) in lung adenocarcinoma. (Modified with permission from Kohno et al.54) Journal of Thoracic Oncology 2018 13, 27-45DOI: (10.1016/j.jtho.2017.10.021) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

Figure 4 Rearranged during transfection proto-oncogene gene (RET) rearrangements by fluorescence in situ hybridization (FISH) analysis (break-apart assay; ZytoLight SPEC RET dual Color Break Apart Probe, Zytovision, CliniSciences, Nanterre, France) in two patients with lung adenocarcinoma. (A) One or two native alleles (N) and a rearranged allele (R) are present. The green spots (probe 3′ RET) and the red spots (probe 5′ RET) are split, revealing a rearrangement of the RET gene. The short distance between the two parts of the probe suggests a rearrangement with kinesin family member 5B gene (KIF5B) on the chromosome 10p. (B) A different pattern of RET rearrangement, with one or two native alleles (N), loss of the 5′ end (red signal) of the RET gene, and concomitant duplication of the derivative chromosome (R). Journal of Thoracic Oncology 2018 13, 27-45DOI: (10.1016/j.jtho.2017.10.021) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

Figure 5 Overall response rates of multikinase inhibitors in patients with rearranged during transfection proto-oncogene gene (RET)-rearranged NSCLC, by study. ∗, Phase I; °, phase II, and ϕ, retrospective. Journal of Thoracic Oncology 2018 13, 27-45DOI: (10.1016/j.jtho.2017.10.021) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

Figure 6 Overall response rates according to rearranged during transfection proto-oncogene gene (RET) fusion variants (kinesin family member 5B gene [KIF5B]-RET versus non–KIF5B-RET) in patients with NSCLC, by study. Journal of Thoracic Oncology 2018 13, 27-45DOI: (10.1016/j.jtho.2017.10.021) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

Figure 7 Escape mechanisms to rearranged during transfection proto-oncogene (RET) inhibition and potential treatment strategies to overcome resistance. RTK, receptor tyrosine kinase; MET, MET proto-oncogene, receptor tyrosine kinase; PI3K, phosphoinositide 3-kinase; AKT2, AKT/serine threonine kinase 2; MAPK, mitogen-activated protein kinase; TKI, tyrosine kinase inhibitor; mTOR, mechanistic target of rapamycin; MDM2, MDM2 proto-oncogene; APC, WNT signaling pathway regulator; mut, mutation. Journal of Thoracic Oncology 2018 13, 27-45DOI: (10.1016/j.jtho.2017.10.021) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions