Darwinian Evolution and Cancer Treatment

One of the first things we learn in Bio 101 is Darwin’s Theory of Evolution. The species we know to exist today are the result of years of natural selection and adaptation, having beaten out their competitors in a match of survival of the fittest. We as humans owe our complexity to this phenomenon. As it turns out, the same phenomenon plays out on a cellular level, and is one of our biggest foes in treating cancer.

As a tumour grows, it acquires secondary mutations, leading to tumour heterogeneity: a tumour made up of ‘subpopulations’ of cells, with different mutations. When treating a tumour with a targeted therapy, the therapy will work on a specific mutation within the gene, typically the activating mutation. The activating mutation is quickly ‘killed off’ through treatment and is no longer an issue. However, as that one mutation can no longer compete, another becomes a forerunner in the tumour, in that same evolutionary fight for survival. If that mutation is not sensitive to the treatment, it will in fact proliferate. In this case, the treatment will no longer have an effect on the tumour and can lead to disease progression. These secondary mutations are known as resistance mutations.

Figure 1: Tumour cell depicting subpopulations and the effect drug-tolerant persister cells can have. Source: Lawson et al., 2018

This acquisition of resistance mutations has been heavily studied in c-KIT mutations that cause Gastrointestinal Stromal Tumours (GIST). Mutations in the c-KIT gene are the most common cause of GISTs, and have been used as biomarkers to test for GIST as they are seen in ~95% of cases (Fletcher, 2016).

Per clinical practice guidelines, patients with GISTs can be treated with the Tyrosine Kinase Inhibitor (TKI) imatinib. This treatment, which has been the go-to in a variety of cancer conditions for over 15 years (Growney et al., 2005), is known to be successful if a patient possesses a mutation exon 11 loci deletions. However, most GIST patients qualifying for imatinib eventually develop resistance mutations such as N822K or D820Y in exon 17. Metastatic GIST patients with resistance to imatinib are typically recommended second generation TKIs such as ripretinib or regorafenib.

The level of evidence for drug recommendations isn’t always consistent. While some drugs are FDA approved for the given variant, others are used as off-label drugs or are currently in clinical trials. Information about the levels of evidence for these activating and resistance mutations and their implications on therapy can be defined, for example, with the AMP Guidelines for Cancer Interpretation.

To be interpreted, a mutation needs not just a drug associated with it, but also whether it’s activating or secondary, and if so what drugs apply in each case, and the level of evidence for the efficacy of that drug. This information is diverse and present across multiple databases: COSMIC and ExAC for somatic and population variants respectively, SIFT and Polyphen to predict variant protein effects, ClinicalTrials.gov for trials, and, of course, a constant stream of publications that report on the effectiveness of the drug.

The ≈16,000 mutations in StrandIRIS combine information from these, and other public sources with levels of evidence associated with a therapy and mutation in an indication. Much of the subtlety in recommending targeted therapy lies in making distinctions between levels of evidence, and accurately associating this with the activating and secondary mutations in the patient.

Learn more about StrandIRIS in this brochure

Bibliography

Fletcher, J.A. (2016). KIT Oncogenic Mutations: Biologic Insights, Therapeutic Advances, and Future Directions. Cancer Res 76, 6140–6142.

Growney, J.D., Clark, J.J., Adelsperger, J., Stone, R., Fabbro, D., Griffin, J.D., and Gilliland, D.G. (2005). Activation mutations of human c-KIT resistant to imatinib mesylate are sensitive to the tyrosine kinase inhibitor PKC412. Blood 106, 721–724.