Overcoming adaptive resistance to anti-VEGF therapy by targeting CD5L

被引：22

作者：

LaFargue, Christopher J. ^{[1
]}

Amero, Paola ^{[2
,3
]}

Noh, Kyunghee ^{[1
,4
]}

Mangala, Lingegowda S. ^{[1
,5
]}

Wen, Yunfei ^{[1
]}

Bayraktar, Emine ^{[1
]}

Umamaheswaran, Sujanitha ^{[1
]}

Stur, Elaine ^{[1
]}

Dasari, Santosh K. ^{[1
]}

Ivan, Cristina ^{[2
]}

Pradeep, Sunila ^{[6
]}

Yoo, Wonbeak ^{[7
]}

Lu, Chunhua ^{[1
]}

Jennings, Nicholas B. ^{[1
]}

Vathipadiekal, Vinod ^{[8
,9
]}

Hu, Wei ^{[1
]}

Chelariu-Raicu, Anca ^{[1
,10
,11
]}

Ku, Zhiqiang ^{[12
]}

Deng, Hui ^{[12
]}

Xiong, Wei ^{[12
]}

Choi, Hyun-Jin ^{[13
,14
]}

Hu, Min ^{[15
]}

Kiyama, Takae ^{[16
]}

Mao, Chai-An ^{[16
,17
]}

Ali-Fehmi, Rouba ^{[18
]}

Birrer, Michael J. ^{[19
]}

Liu, Jinsong ^{[20
]}

Zhang, Ningyan ^{[12
]}

Lopez-Berestein, Gabriel ^{[2
,5
]}

de Franciscis, Vittorio ^{[21
,22
]}

An, Zhiqiang ^{[12
]}

Sood, Anil K. ^{[1
,5
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol & Reprod Med, Houston, TX 77030 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA

[3] CNR, Ist Endocrinol Oncol Sperimentale, Naples, Italy

[4] Korea Res Inst Biosci & Biotechnol, Lab Dis Modeling & Therapeut, Daejeon, South Korea

[5] Univ Texas MD Anderson Canc Ctr, Ctr RNA Interference & Non Coding RNA, Houston, TX 77030 USA

[6] Med Coll Wisconsin, Dept Obstet & Gynecol, Milwaukee, WI 53226 USA

[7] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA

[8] Wave Life Sci, 733 Concord Ave, Cambridge, MA 02138 USA

[9] Alloy Therapeut, Dept Genet Med, Waltham, MA USA

[10] Ludwig Maximilians Univ Munchen, Dept Obstet & Gynecol, Munich, Germany

[11] German Canc Res Ctr, German Canc Consortium DKTK, Munich, Germany

[12] Univ Texas Hlth Sci Ctr Houston, Texas Therapeut Inst, Brown Fdn Inst Mol Med, Houston, TX 77030 USA

[13] Chung Ang Univ, Coll Med, Dept Obstet & Gynecol, Seoul, South Korea

[14] Chung Ang Univ, Coll Med, Gwangmyeong Hosp, Dept Obstet & Gynecol, Seoul, South Korea

[15] Univ Texas MD Anderson Canc Ctr, CPRIT Single Core, Dept Genet, Houston, TX 77030 USA

[16] Univ Texas Hlth Sci Ctr Houston UTHealth, Ruiz Dept Ophthalmol & Visual Sci, McGovern Med Sch, Houston, TX 77030 USA

[17] MD Anderson Canc Ctr, UTHealth Grad Sch Biomed Sci, Houston, TX 77030 USA

[18] Wayne State Univ, Dept Pathol, Detroit, MI 48201 USA

[19] Univ Arkansas Med Sci, Winthrop P Rockefeller Canc Inst, Little Rock, AR USA

[20] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA

[21] Natl Res Council CNR, Inst Genet & Biomed Res IRGB UOS Milan, Via R Levi Montalcini, I-20090 Pieve Emanuele, MI, Italy

[22] Harvard Med Sch, Initiat RNA Med, Boston, MA 02115 USA

来源：

NATURE COMMUNICATIONS | 2023年 / 14卷 / 01期

关键词：

TUMOR ANGIOGENESIS; OVARIAN-CANCER; AIM; EXPRESSION; APOPTOSIS; BEVACIZUMAB; CARCINOMA; PATHWAYS; GROWTH;

D O I：

10.1038/s41467-023-36910-5

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Antiangiogenic treatment targeting the vascular endothelial growth factor (VEGF) pathway is a powerful tool to combat tumor growth and progression; however, drug resistance frequently emerges. We identify CD5L (CD5 antigen-like precursor) as an important gene upregulated in response to antiangiogenic therapy leading to the emergence of adaptive resistance. By using both an RNA-aptamer and a monoclonal antibody targeting CD5L, we are able to abate the pro-angiogenic effects of CD5L overexpression in both in vitro and in vivo settings. In addition, we find that increased expression of vascular CD5L in cancer patients is associated with bevacizumab resistance and worse overall survival. These findings implicate CD5L as an important factor in adaptive resistance to antiangiogenic therapy and suggest that modalities to target CD5L have potentially important clinical utility. The efficacy of antiangiogenic therapy in the clinic is often limited by the emergence of resistance. Here, the authors show that in ovarian cancer anti-VEGF inhibitors induce the overexpression of CD5L in endothelial cells through hypoxia-driven PPARy activation and that blocking CD5L can overcome resistance.

引用

页数：18

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