Genome-based cancer therapeutics: targets, kinase drug resistance and future strategies for precision oncology
Introduction
The 200 or so diseases classified as cancer represent a major and rising global health burden, with 12.7 million newly diagnosed cases and more than 7.5 million deaths each year; thus development of new improved cancer therapies is one of a number of important recommendations proposed recently by an international group to meet the urgent unmet medical need [1]. Until the last decade or so, drug treatment for cancer was dominated by cytotoxic agents which proved effective in malignancies such as childhood leukaemia, testicular and breast cancer but relatively ineffective in others, such as lung, pancreatic, brain and oesophageal tumours, even with drug combinations [2, 3]. More recently, the balance has shifted overwhelmingly to the discovery and development of molecular therapeutics targeted to the genomic and other molecular abnormalities in cancer, offering the promise of greater efficacy and therapeutic selectivity — an approach referred to as ‘drugging the cancer genome’ [4].
While impressive and durable responses are obtained with certain molecularly targeted drugs — most notably the iconic examples of the monoclonal antibody trastuzumab in breast cancers with amplification of the pathogenic HER2/ERBB2 receptor tyrosine kinase target and the small-molecule imatinib that inhibits the translocated BCR-ABL driver tyrosine kinase in chronic myeloid leukaemia (CML) — in most cases the responses to single agent molecular cancer therapeutics are relatively short-lived and intrinsic or acquired drug resistance is now seen as the major obstacle in targeted cancer therapy, just as it has been with cytotoxic agents [5, 6].
In this short article we will describe progress with the current approaches to targeting the cancer genome, review recent findings on resistance to molecularly targeted cancer drugs, assess the molecular mechanisms involved, and discuss circumvention strategies for clinical application. The focus will be on protein kinase inhibitors, reflecting the strong development emphasis and wealth of research on these agents. First we need to assess the current status of the molecular basis of cancer, which increasingly underpins rational approaches to detection, diagnosis and treatment.
Section snippets
Lessons from the cancer genome
A major advance in the understanding and therapeutic targeting of malignancies has come from the comprehensive and ongoing sequencing of thousands of cancer genomes. Two recent articles have provided excellent overviews of the genomic landscape of human cancers and summarized the lessons learned to date [7••, 8••]. Generally, the landscape comprises a relatively small proportion of ‘mountains’ — genes altered in a large proportion of malignancies — and a far greater percentage of ‘hills’ — genes that
Drugging the cancer kinome
The first known oncogene, SRC, is a protein tyrosine kinase identified from research on a chicken cancer virus in the 1970s [2]. Protein kinases and the PI3 lipid kinase family now represent a major focus of drug discovery and development in oncology [20]. A total of 26 small-molecule kinase inhibitors have received regulatory approval, 19 for cancer indications, together with four monoclonal antibodies in oncology. Although a large proportion of pharmaceutical industry effort is focused, in
Resistance to kinase inhibitors
As highlighted earlier, while a number of molecular therapeutics — including many kinase inhibitors following on from imatinib for CML — have extended life sufficiently to gain regulatory approval in solid tumours, the responses have usually not proved to be very durable, with survival extended by only a few months before resistance develops. Following the initial discovery of BCR-ABL kinase inhibitor-resistant alleles that were detected after treatment with imatinib — including ATP-site gatekeeper
Clonal heterogeneity and evolution
The clonal heterogeneity and Darwinian evolutionary behaviour of cancers, involving step-wise somatic cell mutations with sequential subclonal selection, has long been recognised [44••, 56]. However, clonal evolution within cancers has been brought into even sharper focus recently as a result of more sophisticated molecular and genomic analysis and the recognition of the key role of oligoclonal diversity and clonal selection in the development of resistance, with respect to both leukaemias and
Concluding remarks and future prospects
The last two years have seen remarkable continuing advances in our understanding of human cancer biology, accelerated by encyclopaedic genomics profiling via next-generation sequencing, which in turn empowers rapid identification of new diagnostic biomarkers and drug targets, not only readily actionable driver kinases but also other functional target classes [18••] that are druggable, including of note proteins involved in epigenetic deregulation and tumour metabolism. The promise of synthetic
Conflict of interest
PW, BA-L, and PAC are employees of The Institute of Cancer Research, which has a commercial interest in the discovery and development of anticancer drugs, including kinase inhibitors, and operates a rewards to inventors scheme. PW is a former employee of AstraZeneca and declares relevant commercial interactions with Yamanouchi (now Astellas), Piramed Pharma (acquired by Roche), Genentech, Vernalis, Novartis, Chroma Therapeutics, Astex Pharmaceuticals, AstraZeneca, Cyclacel, Onyx
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
PAC, BA-L and PW are grateful for major core support from Cancer Research UK (programme grant C309/A8725). PW is a Cancer Research UK Life Fellow. The authors acknowledge funding to The Institute of Cancer Research and the Royal Marsden Hospital as a Cancer Research UK Centre and from the National Institute of Health Research to our Biomedical Research Centre. We apologize to the authors of numerous excellent papers that could not be cited because of space constraints. We thank our many
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