IGF1R linked to mutation-negative lung cancer erlotinib resistance

By Lynda Williams, Senior medwireNews Reporter

Activation of the insulin-like growth factor 1 receptor (IGF1R) plays a key role in acquired resistance to erlotinib in lung cancer with wild-type epidermal growth factor receptor (EGFR), research suggests.

The study published in the International Journal of Cancer follows recent reports that IGF1R is linked to EGFR tyrosine kinase inhibitor (TKI) resistance in lung cancer with EGFR mutations.

“Therefore, IGF1R is regarded as an important molecular target to prevent or overcome acquired resistance to EGFR-TKIs in lung cancers with and without EGFR mutations,” suggest Kenichi Suda (Kinki University, Osaka, Japan) and co-authors.

The team induced erlotinib resistance in the H358 lung adenocarcinoma cell line, which carries the wild-type EGFR gene but has modest sensitivity to the EGFR-TKI. By growing the cells in increasing concentrations of erlotinib, the researchers were able to increase resistance 28-fold and this was associated with morphological changes to the cells.

Analysis showed that the erlotinib-resistant cells did not have secondary EGFR mutations and did not differ in the expression of EGFR, ERBB2, ERBB3, ERBB4, MET or PTEN. However, while the parent H358 cells lost downstream signalling of Akt and ERK phosphorylation on treatment with erlotinib, these pathways were retained in the erlotinib-resistant cells.

Further analysis revealed that, compared with the parent cells, H358 erlotinib-resistant cells had fivefold greater levels of AXL, a marker of cell adhesion and proliferation, which the researchers believe may explain the differences in the morphological appearances of the two cell lines. However, although AXL was phosphorylated only in the erlotinib-resistant cells, AXL knockdown did not affect downstream signalling.

In addition, erlotinib-resistant cells had an 18-fold increase in IGFR1 phosphorylation. Moreover, when erlotinib-resistant cells were treated with an IGFR1 inhibitor alongside erlotinib, the cells were responsive to the EGFR-TKI. Inhibition of IGFR1 but not EGFR suppressed AKT phosphorylation in the erlotinib-resistant cells.

“Our results indicate that IGF1R activation is a molecular mechanism that confers acquired resistance to erlotinib in lung cancers with the wild-type EGFR,” Suda et al therefore conclude.

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