Rafal Dziadziuszko, MD, PhD, Anh T

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An Activating KIT Mutation Induces Crizotinib Resistance in ROS1-Positive Lung Cancer Rafal Dziadziuszko, MD, PhD, Anh T. Le, BA, Anna Wrona, MD, Jacek Jassem, MD, PhD, D. Ross Camidge, MD, PhD, Marileila Varella-Garcia, PhD, Dara L. Aisner, MD, PhD, Robert C. Doebele, MD, PhD Journal of Thoracic Oncology Volume 11, Issue 8, Pages 1273-1281 (August 2016) DOI: 10.1016/j.jtho.2016.04.001 Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions

Figure 1 Fluorescence in situ hybridization (FISH) analyses for ROS proto-oncogene 1, receptor tyrosine kinase gene (ROS1) and KIT proto-oncogene receptor tyrosine kinase gene (KIT) in patient tumor samples. FISH analysis was performed on the patient’s tumor samples before crizotinib treatment (A and C) and at the time of progression while the patient was receiving crizotinib (B and D). ROS1 break apart FISH demonstrates no gain or loss of ROS1 fusion gene copies in the postcrizotinib sample (B) compared with in the precrizotinib sample (A). The 5’ ROS1 probes are indicated in yellow and 3’ ROS1 probes are indicated in aqua. Normal, unrearranged copies are indicated by white arrows. KIT FISH demonstrates no evidence of KIT gene amplification in the postcrizotinib sample (D) compared with in the pretreatment sample (C). The KIT gene is indicated in red and the centromere enumeration probes from chromosome 4 are indicated in aqua. Journal of Thoracic Oncology 2016 11, 1273-1281DOI: (10.1016/j.jtho.2016.04.001) Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions

Figure 2 Crizotinib resistance in a patient with ROS proto-oncogene 1, receptor tyrosine kinase (ROS1)-positive non–small cell lung cancer. Computed tomography scans demonstrating pretreatment disease (A), response to crizotinib therapy (B) and disease-progression during crizotinib treatment (C) in a patient with ROS1-positive non–small cell lung cancer. (D) Reverse-transcriptase polymerase chain reaction (RT-PCR) of a region of the KIT proto-oncogene receptor tyrosine kinase domain in precrizotinib (Pre-criz) and postcrizotinib (Post-criz) treatment tumor biopsy specimens. The correctly sized PCR product is indicated by an arrow and is only observed in the postcrizotinib tumor sample. (E) Sanger DNA sequencing of the RT-PCR product observed in (D), demonstrating the presence of the mutation c.2447A>G encoding the KIT proto-oncogene receptor tyrosine kinase p.D816G amino acid substitution. Expression of both the wild-type and mutant KIT proto-oncogene receptor tyrosine kinase gene (KIT) mRNA was observed. Journal of Thoracic Oncology 2016 11, 1273-1281DOI: (10.1016/j.jtho.2016.04.001) Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions

Figure 3 The KIT proto-oncogene receptor tyrosine kinase (KIT) mutation KITD816G is an activating mutation and can be inhibited by ponatinib. (A) KITWT, KITD816G, KITD816V, or an empty vector construct was expressed in 293T cells by transient transfection. Cells were treated with 100 ng/mL stem cell factor (SCF) for 20 minutes and/or 500 nM ponatinib for 2 hours where indicated. Protein expression and phosphorylation were measured by Western blot. KITD816G is autophosphorylated in the absence of its cognate ligand SCF and can be inhibited by ponatinib. KITD816V is also autophosphorylated but is inhibited to a lesser degree by ponatinib. (B) Cellular proliferation of Ba/F3 cells expressing WT KIT with or without 100 ng SCF, KITD816G, or KITD816V mutation in the absence of supplemental IL-3 (interleukin-3) was measured by cell counting at the indicated intervals. Cell number was plotted as percent of control (POC) relative to day 0 counts. WT KIT with SCF, KITD816G, and KITD816V induced cell proliferation, whereas WT KIT in the absence of SCF failed to support cellular proliferation. (C) Cell proliferation assays were performed on Ba/F3 cells expressing syndecan 4 (SDC4)–ROS proto-oncogene 1, receptor tyrosine kinase (ROS1), KITD816G, KITD816V, or parental BA/F3 cells supplemented with IL-3 in the presence of the indicated doses of crizotinib (C) or ponatinib (D). Cells were assayed for cell proliferation as described in the Methods section (n = 3, error bars represent ± standard error of the mean). (C) Ba/F3–SDC4-ROS1 cells, but not KITD816G, KITD816V, or BA/F3 parental cells, are sensitive to crizotinib. The concentration of crizotinib that inhibits 50% was calculated for each cell line as follows: Ba/F3–SDC4-ROS1, 112.3 ± 26.7 nM; Ba/F3-KITD816G, 391.2 nM ± 4.7 nM; Ba/F3-KITD816V, 393.8 ± 6.1 nM; Ba/F3 parental + IL-3, 444.5 ± 15.9 nM. (D) Ba/F3-KITD816G and Ba/F3-KITD816V cells, but not SDC4-ROS1 or BA/F3 parental cells, are sensitive to ponatinib. The concentration of ponatinib that inhibits 50% was calculated for each cell line as follows: Ba/F3-KITD816G, 9.9 ± 2.5 nM; Ba/F3-KITD816V, 12.3 nM ± 2.3 nM; Ba/F3–SDC4-ROS1, 73.4 ± 12.2 nM; and Ba/F3 parental + IL-3, 68.3 ± 13.1 nM. pERK1/2, phosphorylated extracellular regulated kinase 1 and 2; ERK1/2, extracellular regulated kinase 1 and 2. Journal of Thoracic Oncology 2016 11, 1273-1281DOI: (10.1016/j.jtho.2016.04.001) Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions

Figure 4 The KIT proto-oncogene receptor tyrosine kinase (KIT) mutation KITD816G induces resistance to crizotinib in ROS proto-oncogene 1, receptor tyrosine kinase–positive cell line models. Human non–small cell lung cancer cell lines CUTO2 (A) and HCC78 (B) were transduced with lentivirus expressing KITD816G (blue) or an empty vector control (red). Cells were treated with the indicated dose range of crizotinib and assayed for cell proliferation as described in the Methods section (n = 3, error bars represent ± standard error of the mean). The concentration that inhibits 50% was calculated for each cell line as follows: CUTO2 EV, 598 ± 110 nM; CUTO2 KITD816G, not reached at 10 μM; HCC78 EV, 872 ±138 nM; and HCC78 KITD816G, 3222 ±138 nM. EV, empty vector; POC, percent of control. Journal of Thoracic Oncology 2016 11, 1273-1281DOI: (10.1016/j.jtho.2016.04.001) Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions

Figure 5 Analysis of signaling in ROS proto-oncogene 1, receptor tyrosine kinase (ROS1)-positive cells harboring the KIT proto-oncogene receptor tyrosine kinase (KIT) mutation KITD816G. Human non–small cell lung cancer cell lines CUTO2 (A and B) and HCC78 (C and D) transduced with lentivirus expressing KITD816G or an empty vector (EV) control. CUTO2 cells were treated with 500 nM crizotinib for 24 hours (A) or 72 hours (B) followed by drug washout for 2 hours. HCC78 cells were treated with 1 μM crizotinib for 24 hours (C) or 72 hours (D) followed by drug washout for 2 hours. Cells were then treated with crizotinib or 500 nM ponatinib for 2 hours as indicated and protein expression and phosphorylation was measured for the indicated proteins. pKIT, phosphorylated KIT proto-oncogene receptor tyrosine kinase; pROS1, phosphorylated ROS proto-oncogene 1, receptor tyrosine kinase; pSHP2, phosphorylated SH2 domain-containing tyrosine phosphatase; pAKT, phosphorylated protein kinase B; AKT, protein kinase B; pERK1/2, phosphorylated extracellular regulated kinase 1 and 2; ERK, extracellular regulated kinase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase. Journal of Thoracic Oncology 2016 11, 1273-1281DOI: (10.1016/j.jtho.2016.04.001) Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions

Figure 6 Combination ROS proto-oncogene 1, receptor tyrosine kinase and KIT proto-oncogene receptor tyrosine kinase (KIT) inhibition overcomes crizotinib resistance mediated by KITD816G. Human non–small cell lung cancer cell lines CUTO2 (A) and HCC78 (B) were transduced with a lentivirus expressing KITD816G and were treated with the indicated dose range of crizotinib alone (blue) or crizotinib plus a fixed dose ponatinib at 500 nM (red). Cells were assayed for cell proliferation as described in the Methods section (n = 3, error bars represent ± standard error of the mean). The concentration that inhibits 50% was calculated for each cell line as follows: for CUTO2-KITD816G and crizotinib only, not reached at 1000 nM; for CUTO2-KITD816G and crizotinib plus ponatinib, 489 ± 29 nM; for HCC78-KITD816G and crizotinib only, >3000 nM; and for HCC78-KITD816G and crizotinib plus ponatinib, 271 ± 12 nM. DMSO, dimethyl sulfoxide; POC, percent of control. Journal of Thoracic Oncology 2016 11, 1273-1281DOI: (10.1016/j.jtho.2016.04.001) Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions