STAT3 Mediates Nilotinib Response in KIT-Altered Melanoma: A Phase II Multicenter Trial of the French Skin Cancer Network Julie Delyon, Sylvie Chevret,

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STAT3 Mediates Nilotinib Response in KIT-Altered Melanoma: A Phase II Multicenter Trial of the French Skin Cancer Network Julie Delyon, Sylvie Chevret, Thomas Jouary, Sophie Dalac, Stephane Dalle, Bernard Guillot, Jean-Philippe Arnault, Marie-Françoise Avril, Christophe Bedane, Guido Bens, Anne Pham-Ledard, Sandrine Mansard, Florent Grange, Laurent Machet, Nicolas Meyer, Delphine Legoupil, Philippe Saiag, Zakia Idir, Victor Renault, Jean-François Deleuze, Elif Hindie, Maxime Battistella, Nicolas Dumaz, Samia Mourah, Celeste Lebbe Journal of Investigative Dermatology Volume 138, Issue 1, Pages 58-67 (January 2018) DOI: 10.1016/j.jid.2017.07.839 Copyright © 2017 The Authors Terms and Conditions

Figure 1 Characteristics of tumor response to nilotinib. (a) Changes in tumor burden from baseline over time according to Response Evaluation Criteria in Solid Tumors. Tumor burden is measured as the sum of the longest diameters of target lesions. Each line represents a patient. The horizontal line at 30% indicates the threshold for defining objective response (partial tumor regression). (b) Kaplan-Meier curves for overall survival (left plot) and progression-free survival (right plot) of patients included. CI, confidence interval; CR, complete response; PR, partial response. Journal of Investigative Dermatology 2018 138, 58-67DOI: (10.1016/j.jid.2017.07.839) Copyright © 2017 The Authors Terms and Conditions

Figure 2 KIT alterations and clinical response to nilotinib. The length of each bar represents the duration of treatment (dark color). Duration of persistent responses after treatment discontinuation is represented with white bars. Black and gray are respectively for patients with good (CR, PR, SD ≥ 3 months) or poor (PD, SD < 3 months) clinical response following Response Evaluation Criteria in Solid Tumors. Patient 4 was treated for 1 year; a local recurrence occurred 9 months after discontinuing nilotinib and was successfully treated with surgery and radiotherapy without relapse so far (CR). Patient 18 experienced PR, and then remained stable while nilotinib was continued out of the study for 3.6 years; SD was still ongoing without any specific treatment for 1 year (March 2017). Patient 21 experienced durable CR for 2.6 years after discontinuing nilotinib, then relapsed in July 2016, and was treated with imatinib. Patient 25 had ongoing SD 4 years after discontinuing nilotinib without any additional treatment. CR, complete response; CSD, melanoma on skin with chronic sun-induced damage; PD, progressive disease; PR, partial response; SD, stable disease; SSM, superficial spreading melanoma. Journal of Investigative Dermatology 2018 138, 58-67DOI: (10.1016/j.jid.2017.07.839) Copyright © 2017 The Authors Terms and Conditions

Figure 3 Level of KIT mutation under treatment with nilotinib. Variation in KIT mutation frequency KIT-M%, defined as the ratio of KIT-mutated allele quantification to the percentage of tumor cells, under treatment with nilotinib, in patients with poor (PD or SD < 3 months) or good (CR, PR, or SD ≥ 3 months) response following Response Evaluation Criteria in Solid Tumors (n = 6). KIT-M% varied from 33 to 100% at baseline, and from 0 to 90% after starting nilotinib (mean time: 3.1 months of treatment). Representative images of c-kit staining detected by immunohistochemistry in two patients at baseline and during follow-up. Scale bar, 25 μm. CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease. Journal of Investigative Dermatology 2018 138, 58-67DOI: (10.1016/j.jid.2017.07.839) Copyright © 2017 The Authors Terms and Conditions

Figure 4 Signaling pathways associated with response to nilotinib in tumors. (a) Tyrosine kinase receptors (PDGFRβ and MET) and growth factors (FGF1 and FGF2), and (b) STAT3 signaling pathway effector (BCL-2, MCL-1, cyclin-D1) mRNA expression, in patients treated with nilotinib with poor (PD or SD < 3 months) (n = 8) or good (CR, PR, or SD ≥ 3 months) (n = 5) response following Response Evaluation Criteria in Solid Tumors. Two time points are plotted: baseline (left) and variation in expression after 1 month of treatment (right). mRNA expression is related to two housekeeping genes (B-ACTIN and PPIA). (c) Ser727-pSTAT3 expression in tumors assessed by in situ proximity ligation assay. Numbers of red signals per cell in tumors are plotted at baseline and under treatment, for patients with poor or good response to nilotinib (n = 4 patients in each group). Representative photographs of pSTAT3 stained as red fluorescent spots in a poor responder (#22) and a good responder (#18), at baseline, and after 1 and 6 months. DAPI stained cell nuclei (blue). Scale bar, 25 μm. Box plot: middle bar, median; lower and upper box limits, 25th and 75th percentiles, respectively; whiskers, min and max values. *P < 0.05; **P < 0.01. CR, complete response; FGF, fibroblast growth factor; MET, mesenchymal epithelial transition; NS, not significant; PD, progressive disease; PR, partial response; SD, stable disease; PDGFR, platelet-derived growth factor receptor; pSTAT3, phosphorylation level of signal transducers and activators of transcription 3. Journal of Investigative Dermatology 2018 138, 58-67DOI: (10.1016/j.jid.2017.07.839) Copyright © 2017 The Authors Terms and Conditions

Figure 5 JAK/STAT signaling pathway in the KIT-mutated melanoma cell line. (a) Immunoblot analyses for the phosphorylation level of STAT3 (pS727-STAT3), AKT, and ERK in KITL576P-mutated M230 cells treated with nilotinib at 0.3 and 1 μmol/l or DMSO as controls for 10 hours (left panel). A longer treatment time (20 hours, right panel) was required to detect a decreased expression level of downstream targets. B-actin was probed as a loading control. (b) Left, immunoblot analyses of the phosphorylation level of STAT3 (pS727-STAT3) in M230 cells treated with nilotinib 0.3 μmol/l, STAT inhibitor SH4-54 2 μmol/l, or DMSO as controls for 10 hours. B-actin was probed as a loading control. Right, proliferation assay of M230 cells treated with nilotinib (0.3 or 1 μmol/l), STAT inhibitor SH4-54 (2, 5, or 10 μmol/l) or DMSO for 96 hours. Bars represent mean ± SD of two experiments performed in triplicate. AKT, acutely transforming retrovirus AKT8 in rodent T-cell lymphoma; ERK, extracellular signal-regulated kinase; JAK, Janus kinase; SD, standard deviation; STAT3, signal transducers and activators of transcription 3. Journal of Investigative Dermatology 2018 138, 58-67DOI: (10.1016/j.jid.2017.07.839) Copyright © 2017 The Authors Terms and Conditions