Co-targeting strategies suggested for EGFR-TKI resistance in NSCLC

Published on July 23, 2014 at 5:15 PM · No Comments

By Lucy Piper, Senior medwireNews Reporter

Researchers have identified additional resistance mechanisms that could be targeted to improve the efficacy of irreversible epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in patients with non-small-cell lung cancer (NSCLC) harbouring both EGFR and T790M mutations.

Preclinical and clinical studies have highlighted the limited efficacy of irreversible EGFR-TKIs, such as afatinib, in patients carrying TKI-sensitive EGFR mutations and the secondary T790M point mutation in exon 20 of EGFR that substitutes methionine for threonine at amino acid position 790.

This suggests that these agents by themselves are insufficient to overcome resistance, the study researchers explain.

To determine strategies to improve on this limited efficacy, 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 with paired PC9GR cells that were EGFR-TKI-resistant and carried T790M.

The researchers found 110 unique anti-phosphotyrosine (pTyr) peptides that were more abundant in the PC9GR cells, many of which corresponded to receptor tyrosine kinases, including AXL and IRS2, which under the correct environmental circumstances could be potential co-drivers of resistance.

There was also a clear sub-network characterised by hyperactive MET signalling, including MET, ROR1 and Gab1/2 proteins. This activated MET signalling was not secondary to MET gene amplification, however.

Abundance of the pTyr peptides in PC9GR cells was amplified by erlotinib treatment. And when PC9GR cells were incubated with ligands of the upregulated receptor tyrosine kinases, those for IRS2 and MET protected the cells against afatinib exposure.

This offers evidence of their ability to cooperate with growth factor ligands to drive resistance to EGFR-TKI, Haura and team write in Clinical Cancer Research.

The researchers then looked for parallel signalling pathways in PC9 and PC9GR cells that were not inhibited by EGFR-TKIs and may cooperate with EGFR to maintain cellular growth and or survival.

They identified an Src family kinase (SFK) network that was EGFR-independent, the phosphorylation of which was unaffected by erlotinib and afatinib, but completely suppressed when exposed to the SFK-inhibitor dasatinib and afatinib.

This potential combined anti-tumour effect of co-targeting SFKs and EGFR T790M was validated in findings showing dasatinib plus afatinib or dasatinib plus T790M-selective EGFR-TKI WZ4002 reduced cell proliferation and increased apoptosis in multiple NSCLC cell lines harbouring T790M. By comparison, there was no combined effect in either EGFR mutated cells or wild-type EGFR cells.

These enhanced anti-tumour effects also translated into improved in vivo effects on tumour growth of PC9GR cells injected into mice.

“Collectively, our results suggest that dasatinib can be generally used as a combination therapy with irreversible or T790M-selective EGFR-TKIs for NSCLC patients who acquired EGFR-TKI resistance associated with T790M”, the researchers report.

They add, however, that its clinical activity in NSCLC treatment is likely to be limited to combinations with T790M-targeted agents and in genotype-specific patients.

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