Vascular Niche Facilitates Acquired Drug Resistance to c-Met Inhibitor in Originally Sensitive Osteosarcoma Cells
Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents characterized by drug resistance and poor prognosis. As one of the key oncogenes, c-Met is recognized as a promising therapeutic target for OS. In this report, we show that c-Met inhibitor PF02341066 specifically kil...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-12-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/24/6201 |
| _version_ | 1797461023334072320 |
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| author | Weifeng Tang Yu Zhang Haixia Zhang Yan Zhang |
| author_facet | Weifeng Tang Yu Zhang Haixia Zhang Yan Zhang |
| author_sort | Weifeng Tang |
| collection | DOAJ |
| description | Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents characterized by drug resistance and poor prognosis. As one of the key oncogenes, c-Met is recognized as a promising therapeutic target for OS. In this report, we show that c-Met inhibitor PF02341066 specifically killed OS cells with highly phosphorylated c-Met in vitro. However, the inhibitory effect of PF02341066 was abrogated in vivo due to interference from the vascular niche. OS cells adjacent to microvessels or forming vascular mimicry suppressed c-Met expression and phosphorylation. Moreover, VEGFR2 was activated in OS cells and associated with acquired drug resistance. Dual targeting of c-Met and VEGFR2 could effectively shrink the tumor size in a xenograft model. c-Met-targeted therapy combined with VEGFR2 inhibition might be beneficial to achieve an ideal therapeutic effect in OS patients. Together, our results confirm the pivotal role of tumor heterogeneity and the microenvironment in drug response and reveal the molecular mechanism underlying acquired drug resistance to c-Met-targeted therapy. |
| first_indexed | 2024-03-09T17:14:30Z |
| format | Article |
| id | doaj.art-8bd8abfb31ee4e0491838f218663f7c8 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T17:14:30Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-8bd8abfb31ee4e0491838f218663f7c82023-11-24T13:47:56ZengMDPI AGCancers2072-66942022-12-011424620110.3390/cancers14246201Vascular Niche Facilitates Acquired Drug Resistance to c-Met Inhibitor in Originally Sensitive Osteosarcoma CellsWeifeng Tang0Yu Zhang1Haixia Zhang2Yan Zhang3MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaMOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaMOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaMOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaOsteosarcoma (OS) is the most common primary bone tumor in children and adolescents characterized by drug resistance and poor prognosis. As one of the key oncogenes, c-Met is recognized as a promising therapeutic target for OS. In this report, we show that c-Met inhibitor PF02341066 specifically killed OS cells with highly phosphorylated c-Met in vitro. However, the inhibitory effect of PF02341066 was abrogated in vivo due to interference from the vascular niche. OS cells adjacent to microvessels or forming vascular mimicry suppressed c-Met expression and phosphorylation. Moreover, VEGFR2 was activated in OS cells and associated with acquired drug resistance. Dual targeting of c-Met and VEGFR2 could effectively shrink the tumor size in a xenograft model. c-Met-targeted therapy combined with VEGFR2 inhibition might be beneficial to achieve an ideal therapeutic effect in OS patients. Together, our results confirm the pivotal role of tumor heterogeneity and the microenvironment in drug response and reveal the molecular mechanism underlying acquired drug resistance to c-Met-targeted therapy.https://www.mdpi.com/2072-6694/14/24/6201osteosarcomac-Metdrug resistancevascular nichetumor heterogeneity |
| spellingShingle | Weifeng Tang Yu Zhang Haixia Zhang Yan Zhang Vascular Niche Facilitates Acquired Drug Resistance to c-Met Inhibitor in Originally Sensitive Osteosarcoma Cells Cancers osteosarcoma c-Met drug resistance vascular niche tumor heterogeneity |
| title | Vascular Niche Facilitates Acquired Drug Resistance to c-Met Inhibitor in Originally Sensitive Osteosarcoma Cells |
| title_full | Vascular Niche Facilitates Acquired Drug Resistance to c-Met Inhibitor in Originally Sensitive Osteosarcoma Cells |
| title_fullStr | Vascular Niche Facilitates Acquired Drug Resistance to c-Met Inhibitor in Originally Sensitive Osteosarcoma Cells |
| title_full_unstemmed | Vascular Niche Facilitates Acquired Drug Resistance to c-Met Inhibitor in Originally Sensitive Osteosarcoma Cells |
| title_short | Vascular Niche Facilitates Acquired Drug Resistance to c-Met Inhibitor in Originally Sensitive Osteosarcoma Cells |
| title_sort | vascular niche facilitates acquired drug resistance to c met inhibitor in originally sensitive osteosarcoma cells |
| topic | osteosarcoma c-Met drug resistance vascular niche tumor heterogeneity |
| url | https://www.mdpi.com/2072-6694/14/24/6201 |
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