Cancer heterogeneity: implications for targeted therapeutics

Abstract

Developments in genomic techniques have provided insight into the remarkable genetic complexity of malignant tumours. There is increasing evidence that solid tumours may comprise of subpopulations of cells with distinct genomic alterations within the same tumour, a phenomenon termed intra-tumour heterogeneity. Intra-tumour heterogeneity is likely to have implications for cancer therapeutics and biomarker discovery, particularly in the era of targeted treatment, and evidence for a relationship between intra-tumoural heterogeneity and clinical outcome is emerging. Our understanding of the processes that exacerbate intra-tumoural heterogeneity, both iatrogenic and tumour specific, is likely to increase with the development and more widespread implementation of advanced sequencing technologies, and adaptation of clinical trial design to include comprehensive tissue collection protocols. The current evidence for intra-tumour heterogeneity and its relevance to cancer therapeutics will be presented in this mini-review.

Figure 1

Serial computed tomography (CT) scans from a patient treated with the mammalian target of rapamycin (mTOR) inhibitor everolimus for metastatic renal cell carcinoma demonstrate a reduction in the size of a metastasis at the medial right lung base (A) but an increase in the size of a metastatic lesion in the left retroperitoneum (B). A differential response such as this may reflect the presence of tumour heterogeneity, or altered pharmacodynamics at separate disease sites.

Figure 2

Trunk-branch model of tumour heterogeneity using single patient examples of renal cell carcinoma (Gerlinger et al, 2012). Ubiquitous driver events are common to all tumour sites and represent the trunk, while the heterogeneous passenger mutations, found at one site of disease but not another, are found in the branches of this model. It seems likely that ‘actionable mutations', that is, those that could be therapeutically targeted and which could serve as useful predictive biomarkers, may prove more tractable when confined to the trunk. However, it is also plausible that heterogeneous minority subpopulation in the branches contribute to treatment resistance and failure, and targeting heterogeneous events in the branches may prove beneficial if paracrine signalling occurs from these subclones stimulating growth of dominant clones. It is also worth noting that in some glioblastoma and breast tumours, genetic events may be present in both the trunk and the branches (Shah et al, 2009).