Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2016;27:1386–422.

Article  PubMed  Google Scholar 

Kindler HL, Friberg G, Skoog L, Wade-Oliver K, Vokes EE. Phase I/II trial of gefitinib and oxaliplatin in patients with advanced colorectal cancer. Am J Clin Oncol. 2005;28:340–4.

Article  CAS  PubMed  Google Scholar 

Bardelli A, Jänne PA. The road to resistance: EGFR mutation and cetuximab. Nat Med. 2012;18:199–200.

Article  CAS  PubMed  Google Scholar 

Yonesaka K, Zejnullahu K, Okamoto I, Satoh T, Cappuzzo F, Souglakos J, et al. Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab. Sci Transl Med. 2011;3:99ra86.

Article  PubMed  PubMed Central  Google Scholar 

Scartozzi M, Mandolesi A, Giampieri R, Bittoni A, Pierantoni C, Zaniboni A, et al. The role of HER-3 expression in the prediction of clinical outcome for advanced colorectal cancer patients receiving irinotecan and cetuximab. Oncologist. 2011;16:53–60.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Sergina NV, Rausch M, Wang D, Blair J, Hann B, Shokat KM, et al. Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature. 2007;445:437–41.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wheeler DL, Huang S, Kruser TJ, Nechrebecki MM, Armstrong EA, Benavente S, et al. Mechanisms of acquired resistance to cetuximab: role of HER (ErbB) family members. Oncogene. 2008;27:3944–56.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Adams R, Brown E, Brown L, Butler R, Falk S, Fisher D, et al. Inhibition of EGFR, HER2, and HER3 signalling in patients with colorectal cancer wild-type for BRAF, PIK3CA, KRAS, and NRAS (FOCUS4-D): a phase 2–3 randomised trial. Lancet Gastroenterol Hepatol. 2018;3:162–71.

Article  PubMed  Google Scholar 

Maughan TS, Adams RA, Smith CG, Meade AM, Seymour MT, Wilson RH, et al. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet. 2011;377:2103–14.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Van Cutsem E, Köhne C, Hitre E, Zaluski J, Chien CC, Makhson A, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360:1408–17.

Article  PubMed  Google Scholar 

Tveit KM, Guren T, Glimelius B, Pfeiffer P, Sorbye H, Pyrhonen S, et al. Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study. J Clin Oncol. 2012;30:1755–62.

Article  CAS  PubMed  Google Scholar 

Bridgewater JA, Pugh SA, Maishman T, Eminton Z, Mellor J, Whitehead A, et al. Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis (New EPOC): long-term results of a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol. 2020;21:398–411.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Santoro V, Jia R, Thompson H, Nijhuis A, Jeffery R, Kiakos K, et al. Role of reactive oxygen species in the abrogation of oxaliplatin activity by cetuximab in colorectal cancer. J Natl Cancer Inst. 2016;108:djv394.

Article  PubMed  Google Scholar 

Bokemeyer C, Kohne C, Ciardiello F, Lenz H, Heinemann V, Klinkhardt U, et al. Treatment outcome according to tumor RAS mutation status in OPUS study patients with metastatic colorectal cancer (mCRC) randomized to FOLFOX4 with/without cetuximab. J Clin Oncol. 2014;32(Suppl 15):abstract 3505.

Douillard J, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013;369:1023–34.

Article  CAS  PubMed  Google Scholar 

Van Cutsem E, Lenz H, Köhne C, Heinemann V, Tejpar S, Melezínek I, et al. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol. 2015;33:692–700.

Article  PubMed  Google Scholar 

Solit DB, She Y, Lobo J, Kris MG, Scher HI, Rosen N, et al. Pulsatile administration of the epidermal growth factor receptor inhibitor gefitinib is significantly more effective than continuous dosing for sensitizing tumors to paclitaxel. Clin Cancer Res. 2005;11:1983–9.

Article  CAS  PubMed  Google Scholar 

Dimco G, Knight RA, Latchman DS, Stephanou A. STAT1 interacts directly with cyclin D1/Cdk4 and mediates cell cycle arrest. Cell Cycle. 2010;9:4638–49.

Article  CAS  PubMed  Google Scholar 

Tang D, Liu CYJ, Shen D, Fan S, Su X, Ye P, et al. Assessment and prognostic analysis of EGFR, HER2, and HER3 protein expression in surgically resected gastric adenocarcinomas. OncoTargets Ther. 2015;8:7–14.

Google Scholar 

Modjtahedi H, Essapen S. Epidermal growth factor receptor inhibitors in cancer treatment: advances, challenges and opportunities. Anticancer Drugs. 2009;20:851–5.

Article  CAS  PubMed  Google Scholar 

Khelwatty SA, Essapen S, Bagwan I, Green M, Seddon AM, Modjtahedi H, et al. Co-expression of HER family members in patients with Dukes’ C and D colon cancer and their impacts on patient prognosis and survival. PLoS ONE. 2014;9:e91139.

Article  PubMed  PubMed Central  Google Scholar 

Holbro T, Beerli RR, Maurer F, Koziczak M, Barbas CF, Hynes NE. The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation. Proc Natl Acad Sci USA. 2003;100:8933–8.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Fruhwirth GO, Fernandes LP, Weitsman G, Patel G, Kelleher M, Lawler K, et al. How Förster resonance energy transfer imaging improves the understanding of protein interaction networks in cancer biology. ChemPhysChem. 2011;12:442–61.

Article  CAS  PubMed  Google Scholar 

Weitsman G, Barber PR, Nguyen LK, Lawler K, Patel G, Woodman N, et al. HER2-HER3 dimer quantification by FLIM-FRET predicts breast cancer metastatic relapse independently of HER2 IHC status. Oncotarget. 2016;7:51012–26.

Article  PubMed  PubMed Central  Google Scholar 

Waterhouse BR, Gijsen M, Barber PR, Tullis IDC, Vojnovic B, Kong A. Assessment of EGFR/HER2 dimerization by FRET-FLIM utilizing Alexa-conjugated secondary antibodies in relation to targeted therapies in cancers. Oncotarget. 2011;2:728–36.

Article  PubMed  PubMed Central  Google Scholar 

Kelleher MT, Fruhwirth G, Patel G, Ofo E, Festy F, Barber PB, et al. The potential of optical proteomic technologies to individualize prognosis and guide rational treatment for cancer patients. Target Oncol. 2009;4:235–52.

Article  PubMed  PubMed Central  Google Scholar 

Ng T, Squire S, Hansra G, Bornancin F, Prevostel C, Hanby A, et al. Imaging protein kinase Cα activation in cells. Science. 1999;283:2085–9.

Article  CAS  PubMed  Google Scholar 

Bosch-Vilaró A, Jacobs B, Pomella V, Abbasi Asbagh L, Kirkland R, Michel J, et al. Feedback activation of HER3 attenuates response to EGFR inhibitors in colon cancer cells. Oncotarget. 2017;8:4277–88.

Article  PubMed  Google Scholar 

Barber PR, Weitsman G, Lawler K, Barrett JE, Rowley M, Rodriguez-Justo M, et al. HER2-HER3 heterodimer quantification by FRET-FLIM and patient subclass analysis of the COIN colorectal trial. J Natl Cancer Inst. 2020;112:944–54.

Article  PubMed  Google Scholar 

Sweeting MJ, Wheeler GM. bcrm: Bayesian continual reassessment method for phase I dose-escalation trials. R package v0.5.4. 2019. https://cran.r-project.org/web/packages/bcrm/index.html.

Hartley JM, Spanswick VJ, Hartley JA. Measurement of DNA damage in individual cells using the single cell gel electrophoresis (Comet) assay. Methods Mol Biol. 2011;731:309–20.

Article  CAS  PubMed  Google Scholar 

Mahajan K, Mahajan NP. Cross talk of tyrosine kinases with the DNA damage signaling pathways. Nucleic Acids Res. 2015;43:10588–601.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Fisher GA, Kuo T, Ramsey M, Schwartz E, Rouse RV, Cho CD, et al. A phase II study of gefitinib, 5-fluorouracil, leucovorin, and oxaliplatin in previously untreated patients with metastatic colorectal cancer. Clin Cancer Res. 2008;14:7074–9.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Corkery B, Crown J, Clynes M, O’Donovan N. Epidermal growth factor receptor as a potential therapeutic target in triple-negative breast cancer. Ann Oncol. 2009;20:862–7.

Article  CAS  PubMed  Google Scholar 

Thomas A, Virdee PS, Eatock M, Lord SR, Falk S, Anthoney DA, et al. Dual Erb B Inhibition in Oesophago-gastric Cancer (DEBIOC): a phase I dose escalating safety study and randomised dose expansion of AZD8931 in combination with oxaliplatin and capecitabine chemotherapy in patients with oesophagogastric adenocarcinoma. Eur J Cancer. 2020;124:131–41.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Freed DM, Bessman NJ, Kiyatkin A, Salazar-Cavazos E, Byrne PO, Moore JO, et al. EGFR ligands differentially stabilize receptor dimers to specify signaling kinetics. Cell. 2017;171:683–95.

Article  CAS  PubMed  PubMed Central