Studying clonal dynamics in response to cancer therapy using high-complexity barcoding

Abstract

Resistance to cancer therapies presents a significant clinical challenge. Recent studies have revealed intratumoral heterogeneity as a source of therapeutic resistance. However, it is unclear whether resistance is driven predominantly by pre-existing or de novo alterations, in part because of the resolution limits of next-generation sequencing. To address this, we developed a high-complexity barcode library, ClonTracer, which enables the high-resolution tracking of more than 1 million cancer cells under drug treatment. In two clinically relevant models, ClonTracer studies showed that the majority of resistant clones were part of small, pre-existing subpopulations that selectively escaped under therapeutic challenge. Moreover, the ClonTracer approach enabled quantitative assessment of the ability of combination treatments to suppress resistant clones. These findings suggest that resistant clones are present before treatment, which would make up-front therapeutic combinations that target non-overlapping resistance a preferred approach. Thus, ClonTracer barcoding may be a valuable tool for optimizing therapeutic regimens with the goal of curative combination therapies for cancer.

Hypermutation signature reveals a slippage and realignment model of translesion synthesis by Rev3 polymerase in cisplatin-treated yeast

“…However, current evidence suggests that resistance mutations are often preexisting in tumor cell populations, and their emergence is a clonal selection process rather than chemotherapy-induced mutations (43). Indeed, even for therapy-related leukemias, p53 mutations driving leukemogenesis were recently found to be preexisting when chemotherapy occurred (44).…”

Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future

“…Indeed, it is likely that many targeted therapies that have successfully passed through the drug development process, demonstrating robust progression free survival benefits in clinical trials, are targeting early clonal events present at all sites of disease. However, even in the context of a clonal driver, resistance to such therapies is frequent in the advanced disease setting and may be driven by the selection of resistance cancer cells present at low frequencies prior to therapy (Bhang et al, 2015;Su et al, 2012;Turke et al, 2010) or may evolve through de novo mutations that are acquired during therapy (Hata et al, 2016).…”

Nominalism in Medicine: the case of personalized medicine or precision medicine

“…22 This heterogeneity is present early in cancer development 23 and -this is consequently important -subclones are selected by cancer treatments. [24][25][26][27][28] Intratumoral genomic heterogeneity represents a severe limit to the potential targeting of mutated pathways on the basis of molecular analysis of a tumor sample. This represents a critical limit to the central concept of precision medicine and explains the therapeutic failure of very high percentage of anticancer drugs.…”