title: Clinical Acquired Resistance to RAF Inhibitor Combinations in BRAF-Mutant Colorectal Cancer through MAPK Pathway Alterations.
abstract: BRAF mutations occur in approximately 10% of colorectal cancers. Although RAF inhibitor monotherapy is highly effective in BRAF-mutant melanoma, response rates in BRAF-mutant colorectal cancer are poor. Recent clinical trials of combined RAF/EGFR or RAF/MEK inhibition have produced improved efficacy, but patients ultimately develop resistance. To identify molecular alterations driving clinical acquired resistance, we performed whole-exome sequencing on paired pretreatment and postprogression tumor biopsies from patients with BRAF-mutant colorectal cancer treated with RAF inhibitor combinations. We identified alterations in MAPK pathway genes in resistant tumors not present in matched pretreatment tumors, including KRAS amplification, BRAF amplification, and a MEK1 mutation. These alterations conferred resistance to RAF/EGFR or RAF/MEK combinations through sustained MAPK pathway activity, but an ERK inhibitor could suppress MAPK activity and overcome resistance. Identification of MAPK pathway reactivating alterations upon clinical acquired resistance underscores the MAPK pathway as a critical target in BRAF-mutant colorectal cancer and suggests therapeutic options to overcome resistance.
  
  
  CONCLUSIONS
  RAF inhibitor combinations represent promising approaches in clinical development for BRAF-mutant colorectal cancer. Initial characterization of clinical acquired resistance mechanisms to these regimens identified several MAPK pathway alterations driving resistance by reactivating MAPK signaling, highlighting the critical dependence of BRAF-mutant colorectal cancers on MAPK signaling and offering potential strategies to overcome resistance.
authors: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors: Leanne G
authors: LG
authors: Ahronian
authors: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors: Erin M
authors: EM
authors: Sennott
authors: Dana Farber Cancer Institute, Boston, Massachusetts. Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
authors: Eliezer M
authors: EM
authors: Van Allen
authors: Dana Farber Cancer Institute, Boston, Massachusetts. Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
authors: Nikhil
authors: N
authors: Wagle
authors: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors: Eunice L
authors: EL
authors: Kwak
authors: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors: Jason E
authors: JE
authors: Faris
authors: Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
authors: Jason T
authors: JT
authors: Godfrey
authors: Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
authors: Koki
authors: K
authors: Nishimura
authors: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors: Kerry D
authors: KD
authors: Lynch
authors: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
authors: Craig H
authors: CH
authors: Mermel
authors: Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
authors: Elizabeth L
authors: EL
authors: Lockerman
authors: Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
authors: Anuj
authors: A
authors: Kalsy
authors: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors: Joseph M
authors: JM
authors: Gurski
authors: Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
authors: Samira
authors: S
authors: Bahl
authors: Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
authors: Kristin
authors: K
authors: Anderka
authors: Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
authors: Lisa M
authors: LM
authors: Green
authors: Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
authors: Niall J
authors: NJ
authors: Lennon
authors: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors: Tiffany G
authors: TG
authors: Huynh
authors: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors: Mari
authors: M
authors: Mino-Kenudson
authors: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
authors: Gad
authors: G
authors: Getz
authors: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors: Dora
authors: D
authors: Dias-Santagata
authors: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors: A John
authors: AJ
authors: Iafrate
authors: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors: Jeffrey A
authors: JA
authors: Engelman
authors: Dana Farber Cancer Institute, Boston, Massachusetts. Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
authors: Levi A
authors: LA
authors: Garraway
authors: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts. rbcorcoran@partners.org.
authors: Ryan B
authors: RB
authors: Corcoran
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005784:Gene Amplification; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D009154:Mutation; D015689:Oncogene Protein p21(ras) / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics*; D015533:Transcriptional Activation
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D015689:Oncogene Protein p21(ras)