Mechanisms of acquired resistance to BRAF V600E inhibition in colon cancers converge on RAF dimerization and are sensitive to its inhibition Journal Article

Authors: Yaeger, R.; Yao, Z.; Hyman, D. M.; Hechtman, J. F.; Vakiani, E.; Zhao, H.; Su, W.; Wang, L.; Joelson, A.; Cercek, A.; Baselga, J.; de Stanchina, E.; Saltz, L.; Berger, M. F.; Solit, D. B.; Rosen, N.
Article Title: Mechanisms of acquired resistance to BRAF V600E inhibition in colon cancers converge on RAF dimerization and are sensitive to its inhibition
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. ©2017 AACR.
Keywords: mitogen activated protein kinase; clinical article; controlled study; human tissue; protein expression; unclassified drug; human cell; cancer growth; nonhuman; mouse; melanoma; enzyme inhibition; gene amplification; gene expression; mitogen activated protein kinase kinase 1; epidermal growth factor receptor; animal experiment; animal model; enzyme activation; tumor xenograft; wild type; cetuximab; cancer resistance; panitumumab; drug mechanism; colon cancer; dimerization; ras protein; guanosine triphosphate; b raf kinase; hygromycin; b raf kinase inhibitor; vemurafenib; colon injury; puromycin; estimated glomerular filtration rate; n [3 (5 chloro 1h pyrrolo[2,3 b]pyridine 3 carbonyl) 2,4 difluorophenyl]propanesulfonamide; human; priority journal; article; alpelisib; bgb 659; encorafenib
Journal Title: Cancer Research
Volume: 77
Issue: 23
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2017-12-01
Start Page: 6513
End Page: 6523
Language: English
DOI: 10.1158/0008-5472.can-17-0768
PROVIDER: scopus
PMCID: PMC5712250
PUBMED: 28951457
Notes: Article -- Export Date: 2 January 2018 -- Source: Scopus
Citation Impact
MSK Authors
  1. Leonard B Saltz
    705 Saltz
  2. Neal Rosen
    399 Rosen
  3. David Solit
    629 Solit
  4. Rona Denit Yaeger
    164 Yaeger
  5. David Hyman
    345 Hyman
  6. Lu Wang
    147 Wang
  7. Michael Forman Berger
    570 Berger
  8. Efsevia Vakiani
    208 Vakiani
  9. Zhan Yao
    37 Yao
  10. Jose T Baselga
    482 Baselga
  11. Jaclyn Frances Hechtman
    196 Hechtman
  12. Wenjing Su
    10 Su
  13. HuiYong   Zhao
    15 Zhao