In Vitro and In Vivo Synergistic Antitumor Activity of the Combination of BKM120 and Erlotinib in Head and Neck Cancer: Mechanism of Apoptosis and Resistance
Authors: Chao Zhang
Zhengjia Chen
Abedul Haque
Zhuo Georgia Chen
Mohammad Aminur Rahman
Dong M Shin
Dongsheng Wang
A R M Ruhul Amin
Abu Syed Md Anisuzzaman
Journal: Molecular Cancer Therapeutics (2017)
Discipline: CLINICAL MEDICINE
Keywords: EGFR; PI3K; apoptosis; SCCHN; synergistic antitumor effects
Affiliations: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia., Department of Biostatistics and Bioinformatics, Emory University, Atlanta, Georgia., Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia. .

Abstract:  We previously reported that the EGFR-targeted inhibitor erlotinib induces G1 arrest of squamous cell carcinoma of the head and neck (SCCHN) cell lines without inducing significant apoptosis. Large-scale genomic studies suggest that &gt;50% of SCCHN cases have activation of PI3K pathways. This study investigated whether cotargeting of EGFR and PI3K has synergistic antitumor effects and apoptosis induction. We examined growth suppression, apoptosis, and signaling pathway modulation resulting from single and combined targeting of EGFR and PI3K with erlotinib and BKM120, respectively, in a panel of SCCHN cell lines and a xenograft model of SCCHN. In a panel of 12 cell lines, single targeting of EGFR with erlotinib or PI3K with BKM120 suppressed cellular growth without inducing significant apoptosis. Cotargeting of EGFR and PI3K synergistically inhibited SCCHN cell line and xenograft tumor growth, but induced variable apoptosis; some lines were highly sensitive, others were resistant. Mechanistic studies revealed that the combination inhibited both axes of the mTORC1 (S6 and 4EBP1) pathway in apoptosis-sensitive cell lines along with translational inhibition of Bcl-2, Bcl-xL, and Mcl-1, but failed to inhibit p-4EBP1, Bcl-2, Bcl-xL, and Mcl-1 in an apoptosis-resistant cell line. siRNA-mediated knockdown of eIF4E inhibited Bcl-2 and Mcl-1 and sensitized this cell line to apoptosis. Our results strongly suggest that cotargeting of EGFR and PI3K is synergistic and induces apoptosis of SCCHN cell lines by inhibiting both axes of the AKT-mTOR pathway and translational regulation of antiapoptotic Bcl-2 proteins. These findings may guide the development of clinical trials using this combination of agents. Mol Cancer Ther; 16(4); 729-38. ©2017 AACR. 

Retracted: No

PubPeer comments:
 Figure 3B appears to have a repeated image. *** ![file] , 
 Thanks for the bring my attention of this matter and appreciate the reviewer s comment. I communicated with the corresponding author who moved to a different institution and he will directly handle this comment and please contact him directly. ARM Ruhul Amin Email: amina@marshall.edu , 
 #2 Thank you for your reply and for contacting the corresponding author at his current email address. , 
 From the corresponding author Dr. Amin After Dr. Shin has provided my new email, I was waiting for a direct correspondence. Since, I have not yet been communicated, I am replying through the link Dr. Shin provided. Thank you very much for capturing this human error. We identified that this a copy paste error happened during compiling the data from microscope for publication. Same image was pasted twice, possibly because pasting without copying the next image or it was not copied. It is our mistake that none of the coauthors or the reviewers was able to catch it. I have already communicated with the journal for a correction. They asked me to submit the corrected figure along with uncropped images. We have uncropped images from all mice and currently compiling the data for sending correction. Ruhul Amin , 
 Correction has been approved by the editors. , 
 2020 correction. https: mct.aacrjournals.org content 19 9 1955 In the original version of this article (1), an IHC image (expression of p-EGFR control) was mistakenly used twice in Fig. 3B. The appropriate BKM panel in the p-EGFR column has replaced the duplicated panel. The error has been corrected in the latest online HTML and PDF versions of the article. The authors regret this error. Reference 1.u21b5Anisuzzaman AS, Haque A, Wang D, Rahmen MA, Zhang C, Chen Z, et al. In vitro and in vivo synergistic antitumor activity of the combination of BKM120 and erlotinib in head and neck cancer: mechanism of apoptosis and resistance. Mol Cancer Ther 2017;16:729u201338 ,