Mechanism of lapatinib-mediated radiosensitization of breast cancer cells is primarily by inhibition of the Raf>MEK>ERK mitogen-activated protein kinase cascade and radiosensitization of lapatinib-resistant cells restored by direct inhibition of MEK.

Abstract

BACKGROUND AND PURPOSE:

We recently showed that lapatinib, an EGFR/HER2 inhibitor, radiosensitized breast cancer cells of the basal and HER2+ subtypes. The purpose of this study was to identify the downstream signaling pathways responsible for lapatinib-mediated radiosensitization in breast cancer.

MATERIALS AND METHODS:

Response of EGFR downstream signaling pathways was assessed by Western blot and clonogenic cell survival assays in breast tumor cells after irradiation (5Gy), lapatinib, CI-1040, or combined treatment.

RESULTS:

In SUM102 cells, an EGFR+ basal breast cancer cell line, exposure to ionizing radiation elicited strong activation of ERK1/2 and JNK, which was blocked by lapatinib, and weak/no activation of p38, AKT or STAT3. Direct inhibition of MEK1 with CI-1040 resulted in 95% inhibition of surviving colonies when combined with radiation while inhibition of JNK with SP600125 had no effect. Lapatinib-mediated radiosensitization of SUM102 cells was completely abrogated with expression of constitutively active Raf. Treatment of lapatinib-resistant SUM185 cells with CI-1040 restored radiosensitization with 45% fewer surviving colonies when combined with radiation.

CONCLUSIONS:

These data suggest that radiosensitization by lapatinib is mediated largely through inhibition of MEK/ERK and that direct inhibition of this pathway may provide an additional avenue of radiosensitization in EGFR+ or HER2+ breast cancers.

• Authors: Maria J Sambade, J Terese Camp, Randall J Kimple, Carolyn I Sartor, Janiel M Shields
• Journal: Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology (Radiother Oncol) Vol. 93 Issue 3 Pg. 639-44 (Dec 2009) ISSN: 1879-0887 [Electronic] Ireland
• PMID: 19853943 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anthracenes
• Quinazolines
• Lapatinib
• pyrazolanthrone
• Mitogen-Activated Protein Kinase 9
• ErbB Receptors
• Receptor, ErbB-2
• Proto-Oncogene Proteins c-raf
• Extracellular Signal-Regulated MAP Kinases
• MAP Kinase Kinase 1
• Mitogen-Activated Protein Kinase Kinases

Topics

• Anthracenes (pharmacology)
• Breast Neoplasms (metabolism, radiotherapy)
• Cell Line, Tumor
• Enzyme Activation (drug effects)
• ErbB Receptors (antagonists & inhibitors)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• Humans
• Lapatinib
• MAP Kinase Kinase 1 (antagonists & inhibitors)
• MAP Kinase Signaling System (drug effects)
• Mitogen-Activated Protein Kinase 9 (antagonists & inhibitors)
• Mitogen-Activated Protein Kinase Kinases (metabolism)
• Proto-Oncogene Proteins c-raf (metabolism)
• Quinazolines (pharmacology)
• Radiation Tolerance (drug effects)
• Receptor, ErbB-2 (antagonists & inhibitors)
• Tumor Cells, Cultured