Nikpour, N. | Search bioRxiv

bioRxiv2022

GIL: A Python package for designing custom indexing primers

Next-generation sequencing allows samples to be multiplexed by adding a unique DNA index to each sample. Multiplexing greatly reduces the price of sequencing large numbers of samples, yet the minimum cost per sample remains high when using commercially available indexing kits and designing custom indexes is challenging. To address these issues, we created GIL (Generate Indexes for Libraries), a software tool that designs indexing primers for producing multiplexed sequencing libraries. GIL can be customized in numerous ways to meet user specifications, including index length, sequencing modality, color balancing, and compatibility with existing primers, and produces ordering and demultiplexing-ready outputs. GIL is written in Python and is freely available on GitHub at https://github.com/de-Boer-Lab/GIL. It can also be accessed as a web-application implemented in Streamlit at https://dbl-gil.streamlitapp.com.

bioinformatics↗

bioRxiv2021

APOBEC3A drives acquired resistance to targeted therapies in non-small cell lung cancer

Acquired drug resistance to even the most effective anti-cancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified1-6, the underlying molecular mechanisms shaping tumor evolution during treatment are incompletely understood. The extent to which therapy actively drives tumor evolution by promoting mutagenic processes7 or simply provides the selective pressure necessary for the outgrowth of drug-resistant clones8 remains an open question. Here, we report that lung cancer targeted therapies commonly used in the clinic induce the expression of cytidine deaminase APOBEC3A (A3A), leading to sustained mutagenesis in drug-tolerant cancer cells persisting during therapy. Induction of A3A facilitated the formation of double-strand DNA breaks (DSBs) in cycling drug-treated cells, and fully resistant clones that evolved from drug-tolerant intermediates exhibited an elevated burden of chromosomal aberrations such as copy number alterations and structural variations. Preventing therapy-induced A3A mutagenesis either by gene deletion or RNAi-mediated suppression delayed the emergence of drug resistance. Finally, we observed accumulation of A3A mutations in lung cancer patients who developed drug resistance after treatment with sequential targeted therapies. These data suggest that induction of A3A mutagenesis in response to targeted therapy treatment may facilitate the development of acquired resistance in non-small-cell lung cancer. Thus, suppressing expression or enzymatic activity of A3A may represent a potential therapeutic strategy to prevent or delay acquired resistance to lung cancer targeted therapy.

cancer biology↗