Abstract

Several tumour types are sensitive to deactivation of just one or very few genes that are constantly active in the cancer cells, a phenomenon that is termed ‘oncogene addiction’. Drugs that target the products of those oncogenes can yield a temporary relief, and even complete remission. Unfortunately, many patients receiving oncogene-targeted therapies relapse on treatment. This often happens due to somatic mutations in the oncogene (‘resistance mutations’). ‘Compound mutations’, which in the context of cancer drug resistance are defined as two or more mutations of the drug target in the same clone may lead to enhanced resistance against the most selective inhibitors. Here, it is shown that the vast majority of the resistance mutations occurring in cancer patients treated with tyrosin kinase inhibitors aimed at three different proteins follow an evolutionary pathway. Using bioinformatic analysis tools, it is found that the drug-resistance mutations in the tyrosine kinase domains of Abl1, ALK and exons 20 and 21 of EGFR favour transformations to residues that can be identified in similar positions in evolutionary related proteins. The results demonstrate that evolutionary pressure shapes the mutational landscape in the case of drug-resistance somatic mutations. The constraints on the mutational landscape suggest that it may be possible to counter single drug-resistance point mutations. The observation of relatively many resistance mutations in Abl1, but not in the other genes, is explained by the fact that mutations in Abl1 tend to be biochemically conservative, whereas mutations in EGFR and ALK tend to be radical. Analysis of Abl1 compound mutations suggests that such mutations are more prevalent than hitherto reported and may be more difficult to counter. This supports the notion that such mutations may provide an escape route for targeted cancer drug resistance.

Highlights

  • The kinase inhibitor (KI) imatinib is prescribed since 2001 to chronic myeloid leukemia (CML) patients [1]

  • The results reveal that drug-resistance mutations in the tyrosine kinase domains of Abelson murine leukemia viral oncogene homolog 1 (Abl1), anaplastic lymphoma kinase (ALK) and exons 20 and 21 of epidermal growth factor receptor (EGFR) favour transformations to residues that can be found in similar positions in evolutionary related proteins

  • Epidermal growth factor receptor Resistance to erlotinib and gefitinib has been linked to six resistance mutations [17,18]

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Summary

Introduction

The kinase inhibitor (KI) imatinib is prescribed since 2001 to chronic myeloid leukemia (CML) patients [1]. Aimed at the tyrosine kinase domain of the abnormal chimeric protein BCR/ Abl, imatinib was the first successful targeted cancer drug. Following its remarkable success and relative safety, additional KIs are administered for treatment of various cancers, and many others are under development [2]. For example, is registered in Sweden for treatment of CML and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+-ALL), various blood syndromes, gastrointestinal stromal tumour (GIST) and dermatofibrosarcoma protuberans (DFSP). The advancement of genome sequencing techniques enables identification of patients that are more likely to benefit from targeted treatment based on the genetic profile of the tumours. New drug targets that are distinct from kinases are being sought after.

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