Liquid Biopsies and Acquired Resistance

- Ethan Cerami

Open any standard cell biology textbook, and you are likely to see a similar diagram describing a cell and its various compartments: DNA coiled into chromosomes, chromosomes tightly packed into the nucleus. The entire cell neatly enclosed in a cellular membrane. According to the model, DNA is cell-bound, uniquely attached to and anchored within a protective and atomic cellular unit.

A group from the Cancer Research UK has successfully applied whole exome sequencing to serial liquid biopsies to identify causes of acquired resistance in multiple cancer types. Image from: M Murtaza, et al. Nature. 2013 May 2;497(7447):108-12.

Except, of course, when it’s not. In 1948, two researchers P. Mandel and P. Metais made the startling discovery that human blood contains free-floating or cell-free DNA [1]. This “naked” DNA, now dubbed circulating free DNA or cfDNA exists is all of us, but researchers have since discovered that certain disease conditions, including rheumatoid arthritis, pancreatitis and cancer can result in increased levels of cfDNA. Where and how this naked DNA originates is still an active area of research, but most now believe it is the result of dying cells releasing their DNA into surrounding tissues. There is also evidence, although no clearly defined mechanism, by which living cells actively shed DNA into circulation [2].

Combine the fact that tumors release naked DNA into the bloodstream with advances in next-generation sequencing, and we now have a new era of “liquid biopsies”. Unlike traditional biopsies, liquid biopsies have the advantage of being non-invasive (no surgery required), and also have the potential to capture multiple sties of tumor growth all at once. Theoretically, liquid biopsies therefore capture both tumor heterogeneity across multiple sites, and tumor evolution across multiple time points.

Multiple applications are on the horizon for liquid biopsies, including the early detection of cancer, and early detection of cancer recurrence. The one area that has seen the greatest advance though is the use of liquid biopsies to identify the cause of acquired resistance, in response to targeted therapy. Every known targeted therapy results in some form of acquired resistance. Bert Vogelstein of Johns Hopkins University has famously called acquired resistance a “fait accompli” [3] – even before targeted therapy begins, a pool of tumor cells already contain the very mutations required to circumvent the therapy, and it is just a matter of time before these cells are selected for, and assert themselves.

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