Co-targeting strategies suggested for resistance to EGFR TKI in NSCLC
By Lucy Piper first medwireNews Problem
resistance mechanisms additional researchers have identified that could be targeted to improve the efficiency of the kinase inhibitors of the receptor tyrosine irreversible epidermal growth factor receptor (EGFR TKI) in patients with non-small cell lung cancer (NSCLC) harboring the two EGFR and T70M mutations.
Preclinical and clinical studies have shown limited effectiveness irreversible EGFR TKI, like afatinib, in patients EGFR TKI sensitive mutations and secondary point mutation T70M in exon 20 of EGFR which replaces methionine for threonine in amino acid position 70.
this suggests that these agents by themselves are not sufficient to overcome the resistance the study researchers explain.
to identify strategies to improve on this limited effectiveness, Eric Haura (H Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA) and colleagues used tyrosine phosphorylation profiling to compare PC9 cells with TKI-sensitive EGFR mutation paired with PC9GR cells that were resistant -TKI EGFR T70M and worn.
researchers found 110 antiphosphotyrosine unique (pTyr), peptides which are more abundant in the cells of PC9GR, many of which corresponded to receptor tyrosine kinases, including AXL and IRS2, which in the correct environmental circumstances could be potential co-drivers resistance.
There was also a clear subnet characterized by hyperactive signaling facility, including TEM, and ROR1 GAB1 2 protein /. This however turned MET signaling is not secondary to amplification MET gene ,.
Abundance of PTyr peptides in PC9GR cells was amplified by the treatment with erlotinib. And when PC9GR cells were incubated with ligands upregulated receptor tyrosine kinases, for those IRS2 MET and protected the cells against afatinib exposure.
This offer proof of their ability to interact with growth factor ligands to lead the resistance to EGFR -TKI, Haura and writing team in Clinical Cancer Research .
The researchers then looked for parallel signaling pathways in the PC9 and PC9GR cells that are not inhibited by EGFR TKI and can cooperate with EGFR to maintain cell growth or survival.
They identified a kinase of the Src family network (SFK) which was independent of EGFR phosphorylation, which was not affected by erlotinib and afatinib, but completely suppressed when exposed the SFK- inhibitor dasatinib and afatinib.
This combined anti-tumor potential effect of SFKs co-targeting EGFR T70M and has been validated in the results showing dasatinib and afatinib or dasatinib, more selective T70M EGFR TKI WZ4002 reduced cell proliferation and increased apoptosis in multiple NSCLC cell lines harboring T70M. By comparison, there was no combination is EGFR mutated cells or wild-type EGFR cells.
These anti-tumor effects also improved resulted in an improvement in vivo effects on tumor growth PC9GR cells injected into mice.
"Collectively, our results suggest that dasatinib can generally be used as a combination therapy with irreversible or selective T70M EGFR TKI for NSCLC patients who acquired EGFR TKI resistance associated with T70M" the researchers reported.
They add, however, that his clinical activity in NSCLC is likely to be limited to combinations with targeted agents and T70M in specific patient genotype.
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