PRKACA mediates resistance to HER2-targeted therapy in breast cancer cells and restores anti-apoptotic signaling.
PRKACA mediates resistance to HER2-targeted therapy in breast cancer cells and restores anti-apoptotic signaling.
复制标题
作者：
在HER2阳性乳腺癌中，用抗体或小分子抑制剂靶向HER2可提高生存率，但耐药性是一个常见的临床问题。为了揭示乳腺癌抗HER2治疗耐药的新机制，我们进行了激酶开放阅读框（ORF）筛选，以鉴定拯救HER2扩增乳腺癌细胞免受HER2抑制或抑制的基因。除了MAPK和PI3K信号通路的多个成员之外，我们发现存活激酶PRKACA和PIM 1的表达从抗HER2治疗中拯救了细胞。此外，我们在曲妥珠单抗耐药的乳腺癌样本中观察到PRKACA表达升高，表明该途径在临床上对含曲妥珠单抗治疗耐药的乳腺癌中被激活。我们发现，在拉帕替尼或曲妥珠单抗治疗后，PRKACA和PIM 1都没有恢复MAPK或PI3K活化，而是灭活了促凋亡蛋白BAD，从而允许通过BCL-XL进行生存信号传导。BCL-XL/BCL-2的药理学阻断部分消除了PRKACA和PIM 1赋予的拯救作用，并使细胞对拉帕替尼治疗敏感。这些观察结果表明，联合靶向HER2和BCL-XL/BCL-2抗凋亡途径可能会增加乳腺癌对抗HER2治疗的反应，并减少耐药疾病的出现。
Targeting HER2 with antibodies or small molecule inhibitors in HER2-positive breast cancer leads to improved survival, but resistance is a common clinical problem. To uncover novel mechanisms of resistance to anti-HER2 therapy in breast cancer, we performed a kinase open reading frame (ORF) screen to identify genes that rescue HER2-amplified breast cancer cells from HER2 inhibition or suppression. In addition to multiple members of the MAPK and PI3K signaling pathways, we discovered that expression of the survival kinases PRKACA and PIM1 rescued cells from anti-HER2 therapy. Furthermore, we observed elevated PRKACA expression in trastuzumab-resistant breast cancer samples, indicating that this pathway is activated in breast cancers that are clinically resistant to trastuzumab-containing therapy. We found that neither PRKACA nor PIM1 restored MAPK or PI3K activation after lapatinib or trastuzumab treatment, but rather inactivated the pro-apoptotic protein BAD, thereby permitting survival signaling through BCL-XL. Pharmacological blockade of BCL-XL/BCL-2 partially abrogated the rescue effects conferred by PRKACA and PIM1, and sensitized cells to lapatinib treatment. These observations suggest that combined targeting of HER2 and the BCL-XL/BCL-2 anti-apoptotic pathway may increase responses to anti-HER2 therapy in breast cancer and decrease the emergence of resistant disease.
登录
查看更多内容
影响因子：
50.5
作者：
Blackwell, K. L.;Pegram, M. D.;Burstein, H. J.
通讯作者：
Burstein, H. J.
影响因子：
4.1
作者：
Lizcano, JM;Morrice, N;Cohen, P
通讯作者：
Cohen, P
影响因子：
45.3
作者：
Cobleigh, MA;Vogel, CL;Slamon, DJ
通讯作者：
Slamon, DJ
影响因子：
5.7
作者：
Nahta, Rita;Yuan, Linda X. H.;Esteva, Francisco J.
通讯作者：
Esteva, Francisco J.
影响因子：
4.8
作者：
Iyer, GH;Moore, MJ;Taylor, SS
通讯作者：
Taylor, SS