Sustained EKR inhibition by EGFR targeting therapies is a predictive factor for synergistic cytotoxicity with PDT as neoadjuvant therapy

• Published in: Biochimica et biophysica acta. General subjects Vol. 1830; no. 3; pp. 2659 - 2670
• Main Authors: Weyergang, Anette, Selbo, Pål K., Berg, Kristian
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.03.2013
• Subjects: adenocarcinoma; adjuvants; antineoplastic agents; cell communication; cell viability; cells; Cetuximab; cytotoxicity; drug resistance; epidermal growth factor receptor (EGFR); epidermal growth factor receptors; Erlotinib; extracellular signal-regulated kinase (ERK); inhibition; mitogen-activated protein kinase; monoclonal antibodies; Photodynamic; therapeutics; Tyrphostin AG1478; Western blotting; PDT; Photodynamic; epidermal growth factor receptor (EGFR); TPPS2a; MTT; EGFR; extracellular signal-regulated kinase (ERK); mAb; Tyrphostin AG1478; TKI; Erlotinib; Cetuximab; ERK
• ISSN: 0304-4165; 1872-8006
• DOI: 10.1016/j.bbagen.2012.11.010

Tyrosin kinase inhibitors (TKIs) and monoclonal antibodies aimed to target epidermal growth factor receptor (EGFR) have shown limited effect as monotherapies and drug resistance is a major limitation for therapeutic success. Adjuvant therapies to EGFR targeting therapeutics are therefore of high clinical relevance. Three EGFR targeting drugs, Cetuximab, Erlotinib and Tyrphostin AG1478 were used in combination with photodynamic therapy (PDT) in two EGFR positive cell lines, A-431 epidermoid skin carcinoma and WiDr colorectal adenocarcinoma cells. The amphiphilic meso-tetraphenylporphine with 2 sulphonate groups on adjacent phenyl rings (TPPS2a) was utilized as a photosensitizer for PDT. The cytotoxic outcome of the combined treatments was evaluated by cell counting and MTT. Cellular signalling was explored by Western blotting. PDT as neoadjuvant to Tyrphostin in A-431 cells as well as to Tyrphostin or Erlotinib in WiDr cells revealed synergistic cytotoxicity. In contrast, Erlotinib or Cetuximab combined with neoadjuvant PDT induced an antagonistic effect on cell survival of A-431 cells. Neoadjuvant PDT and EGFR targeting therapies induced a synergistic inhibition of ERK as well as synergistic cytotoxicity only when the EGFR targeting monotherapies caused a prolonged ERK inhibition. There were no correlation between EGFR inhibition by the EGFR targeting monotherapies or the combined therapies and the cytotoxic outcome combination-therapies. The results suggest that sustained ERK inhibition by EGFR targeting monotherapies is a predictive factor for synergistic cytotoxicity when combined with neoadjuvant PDT. The present study provides a rationale for selecting anticancer drugs which may benefit from PDT as adjuvant therapy. ► We here evaluate PDT as neoadjuvant to EGFR targeting therapeutics. ► Cetuximab, Erlotinib and Tyrphostin were combined with PDT in two cancer cell lines. ► Synergy was observed when the EGFR targeting drug exerted prolonged ERK inhibition. ► Synergistic cytotoxicity was linked to synergistic ERK inhibition.