Downregulation of PDGFRß Signaling Overcomes Crizotinib Resistance in a TYRO3 and ALK Mutated Neuroendocrine-Like Tumor
| Autor: | Andee M. Beierle, Colin H. Quinn, Elizabeth Mroczek-Musulman, Jamie M. Aye, David K. Crossman, Adele P. Williams, Hooper R. Markert, Jerry E. Stewart, Raoud Marayati, Karina J. Yoon, Laura V. Bownes, Elizabeth A. Beierle |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Cancer Research medicine.medical_treatment Receptor expression Targeted therapy 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Crizotinib Neuroendocrine tumor In vivo medicine RC254-282 Original Research business.industry Sunitinib Neoplasms. Tumors. Oncology. Including cancer and carcinogens 030104 developmental biology Oncology 030220 oncology & carcinogenesis Drug resistance Cancer research business Patient derived xenoline TYRO3 medicine.drug |
| Zdroj: | Translational Oncology, Vol 14, Iss 7, Pp 101099-(2021) Translational Oncology |
| ISSN: | 1936-5233 |
| Popis: | Highlights • Rare, high grade neuroendocrine-like pediatric tumor has TYRO3 and ALK mutations. • Crizotinib downregulates STAT3 and ERK1/2 signaling in tumor. • In vivo analysis demonstrated crizotinib resistance. • Crizotinib resistant cells have upregulation of PDGFRß signaling. • PDGFRß inhibition overrides resistance. Patient-derived xenografts provide significant advantages over long-term passage cell lines when investigating efficacy of treatments for solid tumors. Our laboratory encountered a high-grade, metastatic, neuroendocrine-like tumor from a pediatric patient that presented with a unique genetic profile. In particular, mutations in TYRO3 and ALK were identified. We established a human patient-derived xenoline (PDX) of this tumor for use in the current study. We investigated the effect of crizotinib, a chemotherapeutic known to effectively target both TYRO3 and ALK mutations. Crizotinib effectively decreased viability, proliferation, growth, and the metastatic properties of the PDX tumor through downregulation of STAT3 signaling, but expression of PDGFRß was increased. Sunitinib is a small molecule inhibitor of PDGFRß and was studied in this PDX independently and in combination with crizotinib. Sunitinib alone decreased viability, proliferation, and growth in vitro and decreased tumor growth in vivo. In combination, sunitinib was able to overcome potential crizotinib-induced resistance through downregulation of ERK 1/2 activity and PDGFRß receptor expression; consequently, tumor growth was significantly decreased both in vitro and in vivo. Through the use of the PDX, it was possible to identify crizotinib as a less effective therapeutic for this tumor and suggest that targeting PDGFRß would be more effective. These findings may translate to other solid tumors that present with the same genetic mutations. |
| Databáze: | OpenAIRE |
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