journal contribution
posted on 2023-03-31, 01:08 authored by Rona Yaeger, Zhan Yao, David M. Hyman, Jaclyn F. Hechtman, Efsevia Vakiani, HuiYong Zhao, Wenjing Su, Lu Wang, Andrew Joelson, Andrea Cercek, Jose Baselga, Elisa de Stanchina, Leonard Saltz, Michael F. Berger, David B. Solit, Neal Rosen Supplementary Figures 1-5: Supplementary Figure 1 - validation and characterization of acquired genomic alterations, Supplementary Figure 2 - RAS amplification leads to increased RAS-GTP and dimerization of RAF, Supplementary Figure 3 - Increase in NRAS expression is sufficient to cause resistance to RAF/EGFR inhibition in vitro in CRC, Supplementary Figure 4 - Increase in NRAS expression does not cause resistance to RAF inhibition in melanoma, Supplementary Figure 5 - Combined EGFR and RAF dimer inhibitors lead to better inhibition of signaling and tumor growth than RAF dimer inhibitor alone in BRAF V600E CRC.
Funding
NIH
Commonwealth Foundation
The Center for Experimental Therapeutics at Memorial Sloan Kettering Cancer Center
Conquer Cancer Foundation
NCI
History
ARTICLE ABSTRACT
BRAF V600E colorectal cancers are insensitive to RAF inhibitor monotherapy due to feedback reactivation of receptor tyrosine kinase signaling. Combined RAF and EGFR inhibition exerts a therapeutic effect, but resistance invariably develops through undefined mechanisms. In this study, we determined that colorectal cancer progression specimens invariably harbored lesions in elements of the RAS–RAF–MEK–ERK pathway. Genetic amplification of wild-type RAS was a recurrent mechanism of resistance in colorectal cancer patients that was not seen in similarly resistant melanomas. We show that wild-type RAS amplification increases receptor tyrosine kinase-dependent activation of RAS more potently in colorectal cancer than in melanoma and causes resistance only in the former. Currently approved RAF inhibitors inhibit RAF monomers but not dimers. All the drug-resistant lesions we identified activate BRAF V600E dimerization directly or by elevating RAS-GTP. Overall, our results show that mechanisms of resistance converge on formation of RAF dimers and that inhibiting EGFR and RAF dimers can effectively suppress ERK-driven growth of resistant colorectal cancer. Cancer Res; 77(23); 6513–23. ©2017 AACR.
