Combined LIM kinase 1 and p21-Activated kinase 4 inhibitor treatment exhibits potent preclinical antitumor efficacy in breast cancer
Authors: Kang-Sheng Gu
Wei Wei
Teng-Teng Zhang
Wan-Ting Liu
Chen-Chen Zhao
Ying-Ying Du
Cong-Jun Zhang
Yu Lei
Meng-Na Zhan
Yang Jiao
Yi-Yin Zhang
Journal: Cancer Letters (2020)
Discipline: CLINICAL MEDICINE
Keywords: Breast cancer; Estrogen receptor alpha; LIM kinase 1; Targeted therapy; p21-activated kinase 4.
Affiliations: Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui Province, China., Department of Pathology, Zhong-Shan Hospital Affiliated to Fudan University, Shanghai, 200023, China., Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui Province, China. Electronic address: .

Abstract:  LIM kinase 1 (LIMK1) and p21-activated kinase 4 (PAK4) are often over-expressed in breast tumors, which causes aggressive cancer phenotypes and unfavorable clinical outcomes. In addition to the well-defined role in regulating cell division, proliferation and invasion, the two kinases promote activation of the MAPK pathway and cause endocrine resistance through phosphorylating estrogen receptor alpha (ERα). PAK4 specifically phosphorylates LIMK1 and its functional partners, indicating possible value of suppressing both kinases in cancers that over-express PAK4 and/or LIMK1. Here, for the first time, we assessed the impact of combining LIMK1 inhibitor LIMKi 3 and PAK4 inhibitor PF-3758309 in preclinical breast cancer models. LIMK1 and PAK4 pharmacological inhibition synergistically reduced the survival of various cancer cell lines, exhibiting specific efficacy in luminal and HER2-enriched models, and suppressed development and ERα-driven signals in a BT474 xenograft model. In silico analysis demonstrated the cell lines with reliance on LIMK1 were the most prone to be susceptible to PAK4 inhibition. Double LIMK1 and PAK4 targeting therapy can be a successful therapeutic strategy for breast cancer, with a unique efficiency in the subtypes of luminal and HER2-enriched tumors. 

Retracted: No

PubPeer comments:
 *[above]* Figure 5.  The miR-520b inhibits the invasion of the human liver cancer cells. Transwell assay of miR-NC and miR-520b mimics transfected SNU-182 and HepG2 liver cancer cells was performed and showed inhibition of cell invasion . *[below]* Figure 5 from [Wu et al (2020)] .  Apigenin inhibits migration and invasion of the SK-BR-3 cells. The transwell assay of the apigenin-treated SK-BR-3 cells showing inhibition of migration and invasion. Overlaps marked. ![] , 
 *[above]* Figure 5.  The miR-520b inhibits the invasion of the human liver cancer cells. Transwell assay of miR-NC and miR-520b mimics transfected SNU-182 and HepG2 liver cancer cells was performed and showed inhibition of cell invasion . *[below]* Figure 6 from [Wang et al (2020)] .  Transwell assay showing HHIP overexpression inhibits the invasion of HepG2 cells . ![file] , 
 Thanks for your comments. For the first comment, I have submmited our manuscript in August 2, 2019. But I have not find Wu et al s manuscript on breast cancer SK-BR-3 cells. The transwell assay of the apigenin-treated SK-BR-3 cells showing inhibition of migration and invasion looked like pieces of our figure miR-NC in Hep G2 liver cancer cells. For the second comment, I have read the Wang et al s manuscript on liver cancer cells from the beginning to the end. I have not find the NC-figure like ours in their Figure 6 . If you have any query, I can send you primary data. , 
 #3 I agree that Fig 6 of Wang et al (2020) no longer overlaps with Fig 5 from your paper. This is due to the regrettable habit of the editors of J. BUOn, of amending papers to remove evidence of scientific malpractice, without acknowledging this in any way. If we check the version of the paper currently housed at the J. BUOn website, it turns out to have been modified on 20 January 2021: ![file] Copies of the original Figures exist, archived in a record of the paper in SemanticScholar: https: www.semanticscholar.org paper HHIP-gene-overexpression-inhibits-the-growth%2C-and-Wang-Ma ec46c558a4da0b56020d66d63bf2da5e49403107 figure 5 ![file] ![file] , 
 #3  But I have not find Wu et al s manuscript on breast cancer SK-BR-3 cells. It does not seem to be available from the AOMS website at present. I have uploaded a copy to Google Drive, for the convenience of interested readers: https: drive.google.com file d 17U4GW-SxfcglTU8K8meSq-cAQE1KhvgH view?usp=sharing. ![file] Even the Abstract seems to have disappeared, though the Wayback Machine has a copy: https: web.archive.org web 20201213010727 https: www.termedia.pl Apigenin-suppresses-proliferation-and-bone-metastasis-of-human-breast-cancer-cells-by-inducing-apoptosis-autophagy-and-modulation-of-the-MEK-ERK-signalling-pathway,19,41634,0,1.html ![file] , 
 #4 Thanks a lot for your habit. If you have any query, your can email me immediately. dingxiaoyan1981@ccmu.edu.cn Best wishes , 
 #5 This paper does not seem to be currently available from the journal website. I have submmited our manuscript in August 2, 2019. The manuscript was online in 2020. But I have not find Wu et al s manuscript on breast cancer SK-BR-3 cells. The transwell assay of the apigenin-treated SK-BR-3 cells showing inhibition of migration and invasion looked like pieces of our figure miR-NC in Hep G2 liver cancer cells. Untillnow, There was no technology to incorporate the pieces to a whole complete figure without any mark. So I don t why the pieces of our figure depicted in their data. If you have any query, I can send you primary data. Best Wishes. , 
 #7 Dr Ding, it seems that you were the innocent victim of plagiarism. The editors of J.BUOn quietly revised [Wang et al (2020)] to replace your images from that paper. The editors of AoMS have removed [Wu et al (2020)] completely. In both cases, the editors seem to have accepted that the papers used stolen data. I can only offer sympathy. How the papermill that wrote both papers managed to acquire your images, so soon after you submitted your manuscript to *American journal of translational research* - that remains a mystery, but I have theories. , 
 #5 Thanks for your response. I cannot upload the copy. And I don t know how to get a unpublised papaer through the above access. All the evidence and pieces of the figure seem that we are the innocent victim of plagiarism. Thank again for your understanding. Best wishes. ,