Targeting the HGF/MET Axis Counters Primary Resistance to KIT Inhibition in <i>KIT</i>-Mutant Melanoma

Oba, Junna; Kim, Sun‐Hee; Wang, Wei‐Lien; Macedo, Mariana P.; Carapeto, Fernando; McKean, Meredith; Arnam, John Van; Eterovic, Agda Karina; Sen, Shiraj; Kale, Charuta; Yu, Xiaoxing; Haymaker, Cara; Routbort, Mark J.; Haydu, Lauren E.; Bernatchez, Chantale; Lazar, Alexander J.; Grimm, Elizabeth A.; Hong, David S.; Woodman, Scott E.

doi:10.1200/po.18.00055

Cited by 16 publications

(19 citation statements)

References 29 publications

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“…Several of the tumor responses to imatinib were achieved when combined with ICI or chemotherapy, which is consistent with our previous work showing that KIT inhibition can enhance the effect of immune-based treatment in a KITmutant cancer mouse model (Yang et al, 2012). Recently, we demonstrated that TKI therapy is markedly enhanced with concurrent blockade of the HGFeMET axis (Oba et al, 2018). These data indicate that combination approaches will be needed to enhance TKI response in KIT-mutant melanoma.…”

Section: Tyrosine Kinase Inhibitor and Immune Checkpoint Inhibitor Resupporting

confidence: 89%

Tyrosine Kinase Inhibitor and Immune Checkpoint Inhibitor Responses in KIT-Mutant Metastatic Melanoma

McKean

Oba

et al. 2019

Journal of Investigative Dermatology

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Section: Tyrosine Kinase Inhibitor and Immune Checkpoint Inhibitor Resupporting

confidence: 89%

Tyrosine Kinase Inhibitor and Immune Checkpoint Inhibitor Responses in KIT-Mutant Metastatic Melanoma

McKean

Oba

et al. 2019

Journal of Investigative Dermatology

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“…In acral and mucosal melanomas, KIT has been considered to be one of the reasonable therapeutic targets [ 12 , 13 ]. A KIT inhibitor, imatinib, demonstrated its clinical efficacy in phase II studies involving patients with KIT mutations [ 14 – 16 ], although it was not effective in another clinical trials that did not include KIT mutation or amplification in the eligibility criteria [ 17 – 19 ].…”

Section: Introductionmentioning

confidence: 99%

Targeted Therapy and Immunotherapy for Melanoma in Japan

Namikawa¹,

Yamazaki²

2019

Curr. Treat. Options in Oncol.

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Opinion statementMelanoma has several clinically and pathologically distinguishable subtypes, which also differ genetically. Mutation patterns vary among different melanoma subtypes, and efficacy of immune-checkpoint inhibitors differs depending on the subtype of melanoma. In spite of the recent revolution of systemic therapies for advanced melanoma, access to innovative agents is still restricted in many countries. This review article aimed to describe the epidemiology and current status of systemic therapies for melanoma in Japan, where melanoma is rare, but access to innovative agents is available. Acral and mucosal melanomas, which are common in Asian populations, predominantly occur in sun-protected areas and share several biological features. Both the melanomas harbor KIT mutation in approximately 15% of the cases; BRAF or NRAS mutation is found in approximately 10–15% of acral melanoma, but these mutations are less frequent in mucosal melanoma. Combined use of BRAF and MEK inhibitors is one of the standards of care for patients with advanced BRAF-mutant melanoma. In patients with melanoma harboring KIT mutation in exon 11 or 13, KIT inhibitors can be a treatment option; however, none of them have been approved in Japan. Immune-checkpoint inhibitors are expected to be less effective against acral and mucosal melanomas because their somatic mutation burden is lower than those in non-acral cutaneous melanomas. A recently completed phase II trial of nivolumab and ipilimumab combination therapy in 30 Japanese patients with melanoma, including seven with acral and 12 with mucosal melanoma, demonstrated an objective response rate of 43%. Regarding oncolytic viruses, canerpaturev (C-REV, also known as HF10) and talimogene laherparepvec (T-VEC) are currently under review in early phase trials. In the adjuvant setting, dabrafenib plus trametinb combination, nivolumab monotherapy, and pembrolizumab monotherapy were approved in July, August, and December 2018 in Japan, respectively. However, most of the adjuvant phase III trials excluded patients with mucosal melanoma. A phase III trial of adjuvant therapy with locoregional interferon (IFN)-β versus surgery alone is ongoing in Japan (JCOG1309, J-FERON), in which IFN-β is injected directly into the site of the primary tumor postoperatively, so that it would be drained through the untreated lymphatic route to the regional node basin. After the recent approval of these new agents, the JCOG1309 trial will be revised to focus on patients with stage II disease. In conclusion, acral and mucosal melanomas have been treated based on the available medical evidence for the treatment of non-acral cutaneous melanomas. Considering the differences in genetic backgrounds and therapeutic efficacy of immunotherapy, specialized therapeutic strategies for these subtypes of melanoma should be established in the future.

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“…Several lines of evidence point out a prominent role of the MET/HGF axis in tumor progression and resistance to therapy of several malignancies, including malignant melanoma. For example, in a case of acral melanoma with KIT mutation, targeting MET with a selective inhibitor successfully overcame resistance to KIT inhibition, as con rmed also in cell line studies [17]. Another study has established that MAPK pathway inhibition following BRAF inhibitor treatment induced rapid increases in MET and GAB1 expression [18] and MET ampli cation was also observed to co-exist with BRAF hotspot mutations [5].…”

Section: Discussionmentioning

confidence: 82%

Correlation of MET and PD-L1 expression in malignant melanoma

Song

Desar

Pengo

et al. 2020

Preprint

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Background: The proto-oncogene MET, the hepatocyte growth factor (HGF) receptor, is a transmembrane receptor tyrosine kinase (RTK) with a prominent role in tumor metastasis and resistance to anti-cancer therapies. Melanoma demonstrates relatively frequent MET aberrations, including MET gene amplification. Concurrently, PD-L1, with its ability to evade anti-tumor immune responses, has emerged as a prominent therapeutic target in melanoma and other malignancies and its expression is used as a predictive biomarker of response to immunotherapy. Methods: We performed immunohistochemistry analysis of MET and PD-L1 in 18 human melanoma cell lines derived from both primary and metastatic lesions; we then performed the same analysis in a human melanoma tissue microarray (TMA) containing 100 melanocytic lesions, including 42 cutaneous malignant melanomas, 20 mucosal melanoma, 21 metastatic melanomas and 17 benign melanocytic nevi as controls. After color deconvolution, TMA cores were identified and segmented to isolate staining and calculate the percentage of positive cells in each core. Results: Overall, MET expression was higher in metastatic lesions and it was higher in tumors with increased PD-L1 expression. Moreover, a positive correlation between MET and PD-L1 expression was found in metastatic melanoma. Conclusions: These data suggest that testing for expression of these markers should be conducted in patients with melanoma with metastatic disease and selective therapies targeting these proteins should be considered for advanced disease.

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Targeting the HGF/MET Axis Counters Primary Resistance to KIT Inhibition in KIT-Mutant Melanoma

Cited by 16 publications

References 29 publications

Tyrosine Kinase Inhibitor and Immune Checkpoint Inhibitor Responses in KIT-Mutant Metastatic Melanoma

Tyrosine Kinase Inhibitor and Immune Checkpoint Inhibitor Responses in KIT-Mutant Metastatic Melanoma

Targeted Therapy and Immunotherapy for Melanoma in Japan

Correlation of MET and PD-L1 expression in malignant melanoma

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