In the literature: December 2019

The introduction of new high-throughput technologies in oncology and the need to apply precision medicine for cancer patients has led to the detection of several molecular alterations. Among them, activating mutations of ERBB2 have been reported in many solid tumours. In the last years, several clinical trials with covalent tyrosine kinase inhibitors (TKIs) for ERBB2 mutant cancers have been conducted, with different results among several cancer types. In the SUMMIT trial, neratinib was most effective in breast cancer patients, with the majority of responders having tumours with L755S, V777L, or L869R ERBB2 mutations.1 In an elegant article published in C ancer C ell by Robichaux et al ,2 different TKI sensitivities between malignancies might be explained by cancer-specific mutational hotspots. In this experiment, specific exon 20 insertions were associated with neratinib sensitivity in breast cancer patients, nevertheless, these were associated with resistance in other cancer types, demonstrating that there may be other mechanisms underlying these tumour-type-specific differences. The molecular dynamic simulations showed that exon 20 insertion mutations and the exon 19 L755P mutation induced conformational changes that affected the overall size and shape of the drug-binding pocket, justifying the lack of response with the majority of TKIs. To further corroborate these data, in non-small cell lung cancer (NSCLC), where exon 20 insertions frequently occur, patients harbouring ERBB2 exon 20 insertion mutations had response rates of 0%, 11.5% and 18.2% to 18.8% to neratinib, dacomitinib and afatinib, respectively. Moreover, while L755S mutations have been shown to respond to neratinib, L755P mutations are profoundly resistant to both TKIs and antibodies drug-conjugated. Interestingly, when a panel of covalent and non-covalent EGFR and HER2 TKIs was tested against the most common HER2 mutants, it was possible to observe that poziotinib has activity against the most common HER2 variants, including exon 19 and 20 …