HER3 PET Imaging Identifies Dynamic Changes in HER3 in Response to HER2 Inhibition with Lapatinib.
HER3 PET Imaging Identifies Dynamic Changes in HER3 in Response to HER2 Inhibition with Lapatinib.
复制标题
DOI：
10.1007/s11307-021-01619-8
复制
发表时间：
2021-12
影响因子：
3.1
通讯作者：
Mahmood U
中科院分区：
文献类型：
--
作者：
Wehrenberg-Klee E;Sinevici N;Nesti S;Kalomeris T;Austin E;Larimer B;Mahmood U
HER2阳性乳腺癌的标准治疗包括抑制HER2。虽然HER2抑制剂显著改善了治疗结果，但许多患者仍然对治疗持抵制态度。在某些乳腺癌中，对HER2抑制的一个重要内在耐药机制是动态上调HER3。HER2抑制后HER3表达的增加允许通过HER2/HER3异源二聚体持续的生长信号，促进肿瘤逃逸。我们推测，一种非侵入性的方法来成像HER3表达的变化对于识别那些响应HER2抑制而动态上调HER3的乳腺癌将是有价值的。我们进一步假设，这种成像方法可以识别那些将受益于额外的HER3基因敲除的肿瘤。在一组HER2+乳腺癌细胞系中，我们评估了HER2抑制剂拉帕替尼治疗后HER3表达和生存能力的变化。用拉帕替尼治疗的小鼠HER2+乳腺癌模型用基于多肽的HER3特异性PET显像剂[68Ga]HER3P1进行成像，以评估经生物分布证实的肿瘤HER3表达和摄取的动态变化。随后，HER2+细胞系被HER2抑制剂拉帕替尼以及HER3特异性siRNA处理，以评估存活率的变化以及与HER3表达上调的相关性。在所有统计比较中，P<；0.05被认为具有统计学意义。拉帕替尼治疗一组HER2+乳腺癌细胞株增加了耐药细胞系MDA-MB 453中HER3的表达，但不能增加耐药细胞系HCC-1569中HER3的表达。对植入HER2+乳腺癌细胞系MDA-MB453或HCC-1569的小鼠在拉帕替尼治疗前后对[68Ga]HER3P1摄取的评估表明，只有MDA-MB453肿瘤的摄取显著增加，这与体外研究结果一致。HER3基因的额外敲除只增加了拉帕替尼在MDA-MB453细胞中的治疗效果，而不是在肝癌-1569细胞中。HER3 PET成像可用于显示HER2+乳腺癌患者在接受HER2抑制剂治疗时HER3表达的动态变化，并确定哪些患者可能受益于联合应用HER3和HER2抑制剂。
Standard therapy for HER2+ breast cancers includes HER2 inhibition. While HER2 inhibitors have significantly improved therapeutic outcomes, many patients remain resistant to therapy. An important intrinsic resistance mechanism to HER2 inhibition in some breast cancers is dynamic upregulation of HER3. Increase in HER3 expression that occurs in response to HER2 inhibition allows for continued growth signaling through HER2/HER3 heterodimers, promoting tumor escape. We hypothesized that a non-invasive method to image changes in HER3 expression would be valuable to identify those breast cancers that dynamically upregulate HER3 in response to HER2 inhibition. We further hypothesized that this imaging method could identify those tumors that would benefit by additional HER3 knockdown. In a panel of HER2+ breast cancer cell lines treated with the HER2 inhibitor lapatinib, we evaluate changes in HER3 expression and viability. Mouse HER2+ breast cancer models treated with lapatinib were imaged with a peptide-based HER3-specific PET imaging agent [68Ga]HER3P1 to assess for dynamic changes in tumoral HER3 expression and uptake confirmed by biodistribution. Subsequently, HER2+ cell lines were treated with the HER2 inhibitor lapatinib as well HER3-specific siRNA to assess for changes in viability and correlate with HER3 expression upregulation. For all statistical comparisons, P<0.05 was considered statistically significant. Lapatinib treatment of a panel of HER2+ breast cancer cell lines increased HER3 expression in the lapatinib-resistant cell line MDA-MB 453 but not the lapatinib-resistant cell-line HCC-1569. Evaluation of [68Ga]HER3P1 uptake in mice implanted with the HER2+ breast cancer cell lines MDA-MB453 or HCC-1569 prior to and after treatment with lapatinib demonstrated a significant increase in MDA-MB453 tumors only, consistent with in vitro findings. The additional knockdown of HER3 increased therapeutic efficacy of lapatinib only in MDA-MB453 cells, but not in HCC-1569 cells. HER3 PET imaging can be used to visualize dynamic changes in HER3 expression that occur in HER2+ breast cancers with HER2 inhibitor treatment and identify those likely to benefit by the addition of combination HER3 and HER2 inhibition.
登录
查看更多内容
影响因子：
17.1
作者：
Elkabets M;Vora S;Juric D;Morse N;Mino-Kenudson M;Muranen T;Tao J;Campos AB;Rodon J;Ibrahim YH;Serra V;Rodrik-Outmezguine V;Hazra S;Singh S;Kim P;Quadt C;Liu M;Huang A;Rosen N;Engelman JA;Scaltriti M;Baselga J
通讯作者：
Baselga J
影响因子：
50.3
作者：
Junttila, Teemu T.;Akita, Robert W.;Sliwkowski, Mark X.
通讯作者：
Sliwkowski, Mark X.
影响因子：
5.7
作者：
Amin, Dhara N.;Ahuja, Deepika;Moasser, Mark M.
通讯作者：
Moasser, Mark M.
影响因子：
64.8
作者：
Sergina, Natalia V.;Rausch, Megan;Wang, Donghui;Blair, Jimmy;Hann, Byron;Shokat, Kevan M.;Moasser, Mark M.
通讯作者：
Moasser, Mark M.
影响因子：
5.7
作者：
McDonagh, Charlotte F.;Huhalov, Alexandra;Nielsen, Ulrik B.
通讯作者：
Nielsen, Ulrik B.