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JCI:鉴定出一类新蛋白让乳腺癌细胞对酪氨酸激酶抑制物产生耐药性

  1. FAM83A
  2. FAM83B
  3. 受体酪氨酸激酶
  4. 癌细胞
  5. 表皮生长因子受体
  6. 酪氨酸激酶抑制物

来源:生物谷 2012-11-18 23:35

2012年8月15日 讯 /生物谷BIOON/ --对细胞生长途径的异常调节是正常细胞变成癌细胞所必需的。在很多类型的癌症中,细胞生长是由一组被称作受体酪氨酸激酶(receptor tyrosine kinases, RTKs)的酶所促进的。

2012年8月15日 讯 /生物谷BIOON/ --对细胞生长途径的异常调节是正常细胞变成癌细胞所必需的。在很多类型的癌症中,细胞生长是由一组被称作受体酪氨酸激酶(receptor tyrosine kinases, RTKs)的酶所促进的。作为RTKs之一的表皮生长因子受体(epidermal growth factor receptor, EGFR)在30%以上的乳腺癌中是过度表达的,然而,靶向RTKs的药物,即酪氨酸激酶抑制物(tyrosine kinase inhibitors, TKIs)并不能有效地治疗乳腺癌。研究人员认为这些癌细胞通过绕开RTKs和利用其他对TKIs不敏感的酶来逃避TKIs的作用。

根据发表在当前的Journal of Clinical Investigation期刊上的研究论文,两个研究小组鉴定出一对相关的癌基因FAM83A和FAM83B,这一对基因允许乳腺癌细胞对TKIs治疗产生耐药性。美国劳伦斯-伯克利国家实验室研究员Mina Bissell领导的一个研究小组进行人乳腺癌细胞系筛查以便鉴定出让癌细胞对EGFR TKIs产生耐药性。

Bissell和同事们证实FAM83A表达增加会增加癌细胞增殖和浸润的能力,而降低FAM83A表达会延缓小鼠体内的肿瘤生长,并使得癌细胞对TKIs敏感。

美国凯斯西储大学医学院研究员Mark Jackson 和同事们鉴定出FAM83B是一个允许正常人乳腺细胞变成肿瘤细胞的基因。再者,在人肿瘤中FAM83A和FAM83B的表达与病人总存活率下降相关联。归纳在一起,这些研究鉴定出两个可能作为新的治疗靶标的基因。

在随附评论论文中,美国弗吉尼亚医学院研究员Steven Grant 讨论了这项研究对开发出策略来战胜癌症对当前可以获得的TKIs产生耐药性的影响。(生物谷Bioon.com)

本文编译自New class of proteins allows breast cancer cells to evade tyrosine kinase inhibitors

FAM83B mediates EGFR- and RAS-driven oncogenic transformation

Rocky Cipriano1, James Graham1, Kristy L.S. Miskimen1, Benjamin L. Bryson1, Ronald C. Bruntz2, Sarah A. Scott2, H. Alex Brown2, George R. Stark3,4,5 and Mark W. Jackson

Aberrant regulation of growth signaling is a hallmark of cancer development that often occurs through the constitutive activation of growth factor receptors or their downstream effectors. Using validation-based insertional mutagenesis (VBIM), we identified family with sequence similarity 83, member B (FAM83B), based on its ability to substitute for RAS in the transformation of immortalized human mammary epithelial cells (HMECs). We found that FAM83B coprecipitated with a downstream effector of RAS, CRAF. Binding of FAM83B with CRAF disrupted CRAF/14-3-3 interactions and increased CRAF membrane localization, resulting in elevated MAPK and mammalian target of rapamycin (mTOR) signaling. Ablation of FAM83B inhibited the proliferation and malignant phenotype of tumor-derived cells or RAS-transformed HMECs, implicating FAM83B as a key intermediary in EGFR/RAS/MAPK signaling. Analysis of human tumor specimens revealed that FAM83B expression was significantly elevated in cancer and was associated with specific cancer subtypes, increased tumor grade, and decreased overall survival. Cumulatively, these results suggest that FAM83B is an oncogene and potentially represents a new target for therapeutic intervention.

FAM83A confers EGFR-TKI resistance in breast cancer cells and in mice

Sun-Young Lee1,2, Roland Meier1,3, Saori Furuta1, Marc E. Lenburg1,4, Paraic A. Kenny1,5, Ren Xu1,6 and Mina J. Bissell

Breast cancers commonly become resistant to EGFR–tyrosine kinase inhibitors (EGFR-TKIs); however, the mechanisms of this resistance remain largely unknown. We hypothesized that resistance may originate, at least in part, from molecular alterations that activate signaling downstream of EGFR. Using a screen to measure reversion of malignant cells into phenotypically nonmalignant cells in 3D gels, we identified FAM83A as a candidate cancer-associated gene capable of conferring resistance to EGFR-TKIs. FAM83A overexpression in cancer cells increased proliferation and invasion and imparted EGFR-TKI resistance both in cultured cells and in animals. Tumor cells that survived EGFR-TKI treatment in vivo had upregulated FAM83A levels. Additionally, FAM83A overexpression dramatically increased the number and size of transformed foci in cultured cells and anchorage-independent growth in soft agar. Conversely, FAM83A depletion in cancer cells caused reversion of the malignant phenotype, delayed tumor growth in mice, and rendered cells more sensitive to EGFR-TKI. Analyses of published clinical data revealed a correlation between high FAM83A expression and breast cancer patients’ poor prognosis. We found that FAM83A interacted with and caused phosphorylation of c-RAF and PI3K p85, upstream of MAPK and downstream of EGFR. These data provide an additional mechanism by which tumor cells can become EGFR-TKI resistant.

FAM83A and FAM83B: candidate oncogenes and TKI resistance mediators

Steven Grant

The growth and survival of tumor cells can depend upon the expression of a single oncogene, and therapeutically targeting this oncogene addiction has already proven to be an effective approach in fighting cancer. However, it is also clear that cancer cells can adapt and become resistant to therapy through compensatory activation of downstream pathways that relieve the cell of its addicted phenotype. In this issue of the JCI, two groups — Lee et al. and Cipriano et al. — identify two related candidate oncogenes that might both contribute to therapeutic resistance to tyrosine kinase inhibitors (TKIs). If validated, this information could help to identify new targets for therapeutic interventions in breast cancer and possibly other cancers and may also assist in the development of strategies designed to overcome resistance to currently available TKIs.

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