Targeted biologic inhibition of both tumor cell-intrinsic and intercellular CLPTM1L/CRR9-mediated chemotherapeutic drug resistance.
Targeted biologic inhibition of both tumor cell-intrinsic and intercellular CLPTM1L/CRR9-mediated chemotherapeutic drug resistance.
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DOI：
10.1038/s41698-021-00152-9
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发表时间：
2021-03-02
影响因子：
7.9
通讯作者：
James MA
中科院分区：
文献类型：
--
作者：
Parashar D;Geethadevi A;McAllister D;Ebben J;Peterson FC;Jensen DR;Bishop E;Pradeep S;Volkman BF;Dwinell MB;Chaluvally-Raghavan P;James MA
耐药肿瘤的复发是实体肿瘤，尤其是卵巢癌的主要问题。尽管以铂为基础的一线治疗通常完全有效，但大多数卵巢癌女性患者会复发，最终，几乎所有复发疾病的女性都会对铂产生耐药性。同样，固有和获得性耐药都是导致胰腺癌预后不佳的原因。我们以前的工作和其他人的工作已经建立了CLPTM1L(唇腭裂跨膜蛋白1样)/CRR9(顺铂耐药相关蛋白9)作为一种存在于肿瘤细胞表面的细胞保护性癌胚蛋白。我们发现CLPTM1L广泛过表达并聚集在卵巢肿瘤细胞的质膜上，而在正常组织中弱表达或不表达。CLPTM1L的高表达与卵巢浆液性腺癌预后不良有关。在原位同种异体移植和患者来源的顺铂耐药异种移植模型中，使用抑制CLPTM1L的人单克隆生物制剂，实现了耐药卵巢癌细胞对铂类药物的强劲再敏化。此外，我们还证明，除了CLPTM1L对细胞自主的细胞保护外，细胞外CLPTM1L还以胞外依赖的方式对化疗杀伤产生抵抗，并且这种细胞间耐药机制可被抗CLPTM1L生物制品抑制。特别是，来自顺铂耐药的卵巢癌细胞系的胞外体CLPTM1L在药物敏感的亲本细胞系中对顺铂具有耐药性。CLPTM1L存在于肿瘤培养上清液的胞外小泡部分和患者血清中，且随着化疗的进行而增加。这些发现对于使用抗CLPTM1L靶向生物制品治疗耐药肿瘤具有令人鼓舞的意义。
Recurrence of therapy-resistant tumors is a principal problem in solid tumor oncology, particularly in ovarian cancer. Despite common complete responses to first line, platinum-based therapies, most women with ovarian cancer recur, and eventually, nearly all with recurrent disease develop platinum resistance. Likewise, both intrinsic and acquired resistance contribute to the dismal prognosis of pancreatic cancer. Our previous work and that of others has established CLPTM1L (cleft lip and palate transmembrane protein 1-like)/CRR9 (cisplatin resistance related protein 9) as a cytoprotective oncofetal protein that is present on the tumor cell surface. We show that CLPTM1L is broadly overexpressed and accumulated on the plasma membrane of ovarian tumor cells, while weakly or not expressed in normal tissues. High expression of CLPTM1L is associated with poor outcome in ovarian serous adenocarcinoma. Robust re-sensitization of resistant ovarian cancer cells to platinum-based therapy was achieved using human monoclonal biologics inhibiting CLPTM1L in both orthotopic isografts and patient-derived cisplatin resistant xenograft models. Furthermore, we demonstrate that in addition to cell-autonomous cytoprotection by CLPTM1L, extracellular CLPTM1L confers resistance to chemotherapeutic killing in an ectodomain-dependent fashion, and that this intercellular resistance mechanism is inhibited by anti-CLPTM1L biologics. Specifically, exosomal CLPTM1L from cisplatin-resistant ovarian carcinoma cell lines conferred resistance to cisplatin in drug-sensitive parental cell lines. CLPTM1L is present in extracellular vesicle fractions of tumor culture supernatants and in patients’ serum with increasing abundance upon chemotherapy treatment. These findings have encouraging implications for the use of anti-CLPTM1L targeted biologics in the treatment of therapy-resistant tumors.
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影响因子：
3.8
作者：
Jagadish N;Parashar D;Gupta N;Agarwal S;Suri V;Kumar R;Suri V;Sadasukhi TC;Gupta A;Ansari AS;Lohiya NK;Suri A
通讯作者：
Suri A
影响因子：
--
作者：
Crow J;Atay S;Banskota S;Artale B;Schmitt S;Godwin AK
通讯作者：
Godwin AK
影响因子：
4.2
作者：
Colombo, Jucimara;Fachel, Angela A.;Rahal, Paula
通讯作者：
Rahal, Paula
影响因子：
11.2
作者：
James MA;Vikis HG;Tate E;Rymaszewski AL;You M
通讯作者：
You M
影响因子：
8.8
作者：
Parashar, Deepak;Geethadevi, Anjali;Chaluvally-Raghavan, Pradeep
通讯作者：
Chaluvally-Raghavan, Pradeep