CRIPTO1 expression in EGFR-mutant NSCLC elicits intrinsic EGFR-inhibitor resistance
Authors: Caterina Bianco
Liam C Lee
Ji Luo
Tetsuya Mitsudomi
Liqiang Xi
Deepa Subramaniam
Kang-Seo Park
Trung Pham
Mark Raffeld
Yisong Wang
Giuseppe Giaccone
Isamu Okamoto
Yasushi Yatabe
Yong Wha Moon
Tony Mok
David S Salomon
Rafael Rosell
Journal: Journal of Clinical Investigation (2014)
Discipline: CLINICAL MEDICINE
Keywords: NSCLC; EGFR; TKI; CRIPTO1; resistance

Abstract:  The majority of non-small cell lung cancer (NSCLC) patients harbor EGFR-activating mutations that can be therapeutically targeted by EGFR tyrosine kinase inhibitors (EGFR-TKI), such as erlotinib and gefitinib. Unfortunately, a subset of patients with EGFR mutations are refractory to EGFR-TKIs. Resistance to EGFR inhibitors reportedly involves SRC activation and induction of epithelial-to-mesenchymal transition (EMT). Here, we have demonstrated that overexpression of CRIPTO1, an EGF-CFC protein family member, renders EGFR-TKI-sensitive and EGFR-mutated NSCLC cells resistant to erlotinib in culture and in murine xenograft models. Furthermore, tumors from NSCLC patients with EGFR-activating mutations that were intrinsically resistant to EGFR-TKIs expressed higher levels of CRIPTO1 compared with tumors from patients that were sensitive to EGFR-TKIs. Primary NSCLC cells derived from a patient with EGFR-mutated NSCLC that was intrinsically erlotinib resistant were CRIPTO1 positive, but gained erlotinib sensitivity upon loss of CRIPTO1 expression during culture. CRIPTO1 activated SRC and ZEB1 to promote EMT via microRNA-205 (miR-205) downregulation. While miR-205 depletion induced erlotinib resistance, miR-205 overexpression inhibited CRIPTO1-dependent ZEB1 and SRC activation, restoring erlotinib sensitivity. CRIPTO1-induced erlotinib resistance was directly mediated through SRC but not ZEB1; therefore, cotargeting EGFR and SRC synergistically attenuated growth of erlotinib-resistant, CRIPTO1-positive, EGFR-mutated NSCLC cells in vitro and in vivo, suggesting that this combination may overcome intrinsic EGFR-inhibitor resistance in patients with CRIPTO1-positive, EGFR-mutated NSCLC. 

Retracted: No

PubPeer comments:
 Figure 1B. * Red boxes: Two CRIPTO1 panels appear to look identical ![file] False color version: ![file] , 
 I contacted the first author Kang-seo Park, post-doc who did the experiment, and who has been back to Korea for several years. Here is the original Fig. 1B that he sent me, which was also requested by JCI at the time of submission, and which is still on the JCI website. He confirmed that he duplicated the first picture (H838 to H3123) in the third picture (CORL23 to H2810), by mistake. The results remain unchanged. We can certainly ask JCI to issue a corrigendum, although I would rather avoid it since this will really not affect the conclusions. after several attempts to attach the file, I am not able to do it, because it looks like it is a different format from what you accept. I can send you the figure as an attachment to an email if you give me your email or another site where a different format is accepted. , 
 Dear Dr. Giaccone, thank you for your reply - much appreciated. The PubPeer platform only allows images 1 MB, but if the image is larger, you can e.g. use Imgur or a Dropbox or Google Drive link to post the images here. Thank you. , 
 ![file] does this work ? , 
 This is perfect, thank you so much, Dr. Giaccone for posting this file. I will leave the decision to issue a correction up to the Editor and you, but I am grateful that you posted this so quickly. Thank you! , 
 #5 I am grateful to you actually. Your work is very important. The issue of data fabrication is becoming more alarming every day. Journals (especially the better ones) will have to invest more in the type of work that you do after articles are already published, in trying to prevent fraud. ,