Differential sensitivity of cancer cells to inhibitors of the epidermal growth factor receptor family.

Abstract

Clinical responses to the HER1 (EGF receptor) inhibitors and HER2/neu/ErbB2 inhibitors correlate with high levels of receptor expression. However, a significant subset of patients with high receptor levels appear to be refractory to treatment. We have observed similar results in the 60 cell lines of the NCI Anti-Cancer Drug Screen using a panel of 11 selective HER1 inhibitors. As expected, low HER1-expressing cell lines were insensitive to HER1 inhibitors. In cell lines with high HER1 expression, low concentrations of HER1 inhibitors potently inhibit both HER1 phosphorylation and the mitogen-activated protein kinase (MAPK) pathway. However, this inhibition did not always correlate with cellular arrest. High HER1-expressing cell lines can be subdivided into two groups based on their sensitivity to HER1 inhibitors. In the sensitive group, receptor and growth inhibition was concordant and occurred at sub-micromolar concentrations of HER1 inhibitors. In the insensitive group, receptor inhibition occurred at a low concentration (< 1 microM) but concentrations that were ten times or higher were required for growth inhibition. Also, neither induction of p21 and cyclin D1 nor p53 status could explain the difference between sensitive and insensitive cells. Although EGF activated the MAPK pathway in all cell lines, only drug-sensitive cell lines responded to EGF (accelerated entry from G1 to S) and to HER1 inhibitors (G1 arrest) by changes in cell cycling. Furthermore, an EGF-dependent immortalized mammary epithelial cell line was extremely sensitive to a panel of HER1 inhibitors. We infer that independence from mitogen-mediated signaling confers insensitivity to HER1 inhibitors in a large subset of cancer cell lines.

• Authors: Philippe C Bishop, Timothy Myers, Robert Robey, David W Fry, Edison T Liu, Mikhail V Blagosklonny, Susan E Bates
• Journal: Oncogene (Oncogene) Vol. 21 Issue 1 Pg. 119-27 (Jan 03 2002) ISSN: 0950-9232 [Print] England
• PMID: 11791182 (Publication Type: Comparative Study, Journal Article)

Chemical References

• CDKN1A protein, human
• Cyclin-Dependent Kinase Inhibitor p21
• Cyclins
• Enzyme Inhibitors
• Neoplasm Proteins
• Pyrimidines
• Quinazolines
• Transforming Growth Factor alpha
• Tumor Suppressor Protein p53
• Tyrphostins
• Cyclin D1
• RTKI cpd
• ErbB Receptors
• Receptor, ErbB-2

Topics

• Cell Cycle (drug effects)
• Cell Line, Transformed (drug effects, enzymology)
• Cyclin D1 (metabolism)
• Cyclin-Dependent Kinase Inhibitor p21
• Cyclins (metabolism)
• Drug Resistance, Neoplasm
• Enzyme Induction (drug effects)
• Enzyme Inhibitors (pharmacology)
• ErbB Receptors (antagonists & inhibitors, physiology)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• MAP Kinase Signaling System (drug effects)
• Male
• Neoplasm Proteins (antagonists & inhibitors, physiology)
• Neoplasms (enzymology, pathology)
• Pyrimidines (pharmacology)
• Quinazolines (pharmacology)
• Receptor, ErbB-2 (antagonists & inhibitors, physiology)
• Transforming Growth Factor alpha (antagonists & inhibitors, physiology)
• Tumor Cells, Cultured (drug effects, enzymology)
• Tumor Suppressor Protein p53 (metabolism)
• Tyrphostins (pharmacology)