Abstract
We set out to study the key effectors of resistance and sensitivity to ErbB2 tyrosine kinase inhibitors, such as lapatinib in ErbB2-positive breast and lung cancers. A cell-based in vitro site-directed mutagenesis lapatinib resistance model identified several mutations, including the gatekeeper ErbB2 mutation ErbB2-T798I, as mediating resistance. ErbB2-T798I engineered cell models indeed show resistance to lapatinib but remain sensitive to the irreversible EGFR/ErbB2 inhibitor, PD168393, suggestive of potential alternative treatment strategies to overcome resistance. Gene expression profiling studies identified a select group of downstream targets regulated by ErbB2 signaling and define PHLDA1 as an immediately downregulated gene upon oncogenic ErbB2 signaling inhibition. We find significant down-regulation of PHLDA1 in primary breast cancer and PHLDA1 is statistically significantly less expressed in ErbB2 negative compared with ErbB2 positive tumors consistent with its regulation by ErbB2. Lastly, PHLDA1 overexpression blocks AKT signaling, inhibits cell growth and enhances lapatinib sensitivity further supporting an important negative growth regulator function. Our findings suggest that PHLDA1 might have key inhibitory functions in ErbB2 driven lung and breast cancer cells and a better understanding of its functions might point at novel therapeutic options. In summary, our studies define novel ways of modulating sensitivity and resistance to ErbB2 inhibition in ErbB2-dependent cancers.
Highlights
ErbB2 is a cell membrane surface-bound receptor tyrosine kinase and is involved in the signal transduction pathways leading to cell growth and proliferation
We showed as expected that both lapatinib as well as the irreversible ErbB2 inhibitor, PD168393 could induce apoptosis and inhibit cell growth in ErbB2 positive lung and breast cancer cell lines
As many imatinib-resistant mutations of BCR-ABL as well as the recently identified D761Y mutation of EGF receptor (EGFR) lead to an IC50 shift in this range, we predict that these mutations will be clinically relevant
Summary
ErbB2 is a cell membrane surface-bound receptor tyrosine kinase and is involved in the signal transduction pathways leading to cell growth and proliferation. This gene is amplified in 10–20% of breast cancers, and amplification results in protein overexpression, which denotes an aggressive phenotype [1,2,3,4]. Overexpression, amplification and occasionally activating mutations of ErbB2 occur in other cancers, including non-small cell lung cancer [5,6]. A dual, reversible EGFR/ ErbB2 inhibitor, lapatinib (Tykerb) in particular has demonstrated significant activity in ErbB2-positive breast cancers and now is approved to be used in this indication [13]. A dual, reversible EGFR/ ErbB2 inhibitor, lapatinib (Tykerb) in particular has demonstrated significant activity in ErbB2-positive breast cancers and now is approved to be used in this indication [13]. http://en.wikipedia. org/wiki/HER2/neu - cite_note-3Inhibition of ErbB2 tyrosine autophosphorylation by lapatinib abrogates downstream Ras-RafERK1/2 and PI3K-AKT growth/survival signaling in ErbB2 overexpressing breast cancer cell lines and in patients with ErbB2overexpressing breast cancers [14]
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