The prevailing paradigm in cancer posits that genetic mutations underpin treatment relapse. Recently, this dogma has been questioned and evidence suggests that epigenetic mechanisms can also contribute to therapeutic escape. Molecular mechanisms governing non-genomic resistance remain elusive, particularly whether resistance occurs through selection of sub-population of pre-existing cells or via transcriptional adaptation as a result of therapeutic pressure.
scRNA-seq of therapy naïve and resistant AML patient samples enabled us to make some key observations about non-genomic resistance. Firstly, the transcriptional program associated with resistance was observed in residual cells at the time of best clinical response. This adaptation allowed these cells to expand in the context of ongoing therapy, resulting in relapse. Secondly, following drug withdrawal, the surviving resistant cells do not revert back to their original transcriptional state and instead, demonstrate several hallmarks of leukemia stem cells. Consistent with non-genomic evolution, pre-therapy clones bearing distinct driver mutations do not show clonal expansion or extinction post therapy, despite the marked transcriptional differences compared with the drug naïve state.
To understand if non-genetic resistance results from dynamic adaptation or selection of a pre-existing transcriptional state, we coupled cellular barcoding with scRNA-seq in a mouse model of non-genetic resistance. These data show that Lamarckian evolution, in the form of gradual transcriptional adaptation, drives stable epigenetic resistance. Additional work from our lab demonstrates that treatment of the cells with an inhibitor of the histone demethylase LSD1 is able to overcome BET inhibitor resistance. LSD1i treatment triggers remodelling of the enhancer landscape, ultimately reinstating the sensitivity of the cells to I-BET. Together, these findings highlight the underappreciated role of transcriptional adaptation in mediating resistance to cancer therapies and provide new molecular insights to help negate this process. On-going work aims to unravel epigenetic states that mediate non-genomic transcriptional adaptation in a broader therapeutic context.