Abstract
Approximately 5-10% of metastatic colorectal cancers harbor a BRAF-V600E mutation, which is correlated with resistance to EGFR-targeted therapies and worse clinical outcome. Vice versa, targeted inhibition of BRAF-V600E with the selective inhibitor PLX 4032 (Vemurafenib) is severely limited due to feedback re-activation of EGFR in these tumors. Mounting evidence indicates that upregulation of the ErbB-3 signaling axis may occur in response to several targeted therapeutics, including Vemurafenib, and NRG-1β-dependent re-activation of the PI3K/AKT survival pathway has been associated with therapy resistance.Here we show that colon CSCs express, next to EGFR and ErbB-2, also significant amounts of ErbB-3 on their membrane. This expression is functional as NRG-1β strongly induces AKT/PKB and ERK phosphorylation, cell proliferation, clonogenic growth and promotes resistance to Vemurafenib in BRAF-V600E mutant colon CSCs. This resistance was completely dependent on ErbB-3 expression, as evidenced by knockdown of ErbB-3. More importantly, resistance could be alleviated with therapeutic antibody blocking ErbB-3 activation, which impaired NRG-1β-driven AKT/PKB and ERK activation, clonogenic growth in vitro and tumor growth in xenograft models. In conclusion, our findings suggest that targeting ErbB-3 receptors could represent an effective therapeutic approach in BRAF-V600E mutant colon cancer.
Highlights
Colorectal cancer (CRC) accounts for almost 10% of all cancers and it is the third most common cancer worldwide and still a major cause of cancer-related deaths [1]
Proliferation (Figure 1C) and clonogenicity (Figure 1D) of cells cultured in the absence www.impactjournals.com/oncotarget of growth factors was strongly inhibited by the drug; this block was completely rescued by addition of exogenous EGF, confirming the previously reported role of EGFR signaling [14] in resistance to Vemurafenib
While no significant changes in EGFR expression were observed between control and Vemurafenib treated samples, we detected a significant increase in the expression of ErbB-3 (Supplementary Figure 1C)
Summary
Colorectal cancer (CRC) accounts for almost 10% of all cancers and it is the third most common cancer worldwide and still a major cause of cancer-related deaths [1]. A multitude www.impactjournals.com/oncotarget of targeted therapeutics have been developed to block the activity of these receptors [3] and over the past decades the development of EGFR targeted therapeutics has improved the clinical outcome of metastatic CRC patients [4]. Despite these encouraging results, the reason why some patients respond to treatment, while others don’t remains poorly understood. Accumulating evidence suggests that, next to pathway mutations, other receptor/ligand pairs may substitute the loss of EGF/EGFR signaling and play a crucial role in anti-EGFR therapy resistance. NRG-1β, the ligand for ErbB-3, is released by tumor-associated stromal cells and has been suggested to promote CRC progression as well as compensate for loss of EGF/EGFR signaling [13]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
