Different responses of colorectal cancer cells to alternative sequences of cetuximab and oxaliplatin

Abstract

Therapeutic protocols including EGFR antibodies in the context of oxaliplatin-based regimens have variable clinical effect in colorectal cancer. Here, we tested the effect of the EGFR antibody cetuximab in different sequential combinations with oxaliplatin on the growth of colorectal cancer cells in vitro and in vivo. Cetuximab reduced the efficacy of oxaliplatin when administered before oxaliplatin but provided additive effect when administered after oxaliplatin regardless of the KRAS or BRAF mutation status of the cells. Systemic gene expression and protein phosphorylation screens revealed alternatively activated pathways regulating apoptosis, cell cycle and DNA damage response. Functional assays indicated that cetuximab-induced arrest of the cells into the G1 phase of the cell cycle was associated with reduced responsiveness of the cells to subsequent treatment with oxaliplatin. In contrast, oxaliplatin-enhanced responsiveness to subsequent treatment with cetuximab was associated with increased apoptosis, inhibition of STAT3 activity and increased EGFR down-regulation. This preclinical study indicates that optimizing the sequence of administration may enhance the antitumor effect of combination therapy with EGFR antibodies and oxaliplatin.

Panitumumab-DOTA-111In: An Epidermal Growth Factor Receptor Targeted Theranostic for SPECT/CT Imaging and Meitner–Auger Electron Radioimmunotherapy of Triple-Negative Breast Cancer

“…EGFR-targeted MAE RIT with 125 I-labeled mouse monoclonal m225 anti-EGFR antibody similarly caused G2/M cell cycle arrest in EGFR-positive human colorectal carcinoma HCT 116 cells . Although EGFR inhibition with small-molecule inhibitors and monoclonal antibodies has been reported to cause G1 arrest, , we found no difference in cell cycle distribution after treatment with panitumumab. A 1.8- and 3.2-fold increase in the SubG1 population of MDA-MB-231/Luc and MDA-MB-468 cells, respectively, suggested the presence of micronuclei or apoptotic cells. , This was further investigated by studying panitumumab-DOTA- 111 In for inducing apoptosis.…”

“…MAE-induced DSB may activate p53 causing cell cycle arrest or apoptosis. 44 44 Although EGFR inhibition with small-molecule inhibitors and monoclonal antibodies has been reported to cause G1 arrest, 45,46 we found no difference in cell cycle distribution after treatment with panitumumab. A 1.8-and 3.2-fold increase in the SubG1 population of MDA-MB-231/Luc and MDA-MB-468 cells, respectively, suggested the presence of micronuclei or apoptotic cells.…”

Cetuximab-induced natural killer cell cytotoxicity in head and neck squamous cell carcinoma cell lines: investigation of the role of cetuximab sensitivity and HPV status

“…A possible explanation for the time-dependent cytotoxic effect of cetuximab could be, as suggested by Narvi et al, that initial/short-term treatment with cetuximab mostly promotes cell cycle arrest, while a sustained inhibition of EFGR signalling initiates apoptotic signalling pathways. 30 …”

Combination Treatment With Paclitaxel, Carboplatin, and Cetuximab (PCE) as First-Line Treatment in Patients With Recurrent and/or Metastatic Nasopharyngeal Carcinoma

“…The drugs used in the PCE regimen collaboratively facilitate tumor apoptosis using different pathways. For example, Cmab promotes cell cycle arrest and activation of proapoptotic molecules through the inhibition of EGFR signaling, taxanes inhibit microtubule disassembly, and platinum agents form DNA adducts (14)(15)(16). GEM and platinum combination is also reported to have synergetic cytotoxicity via the inhibition of DNA synthesis and increasing cell apoptosis (17).…”