Clinical data revealed that KRAS mutant tumors, while initially sensitive to treatment, rapidly bypass KRAS dependence to acquire a drug-tolerant phenotype. However, the mechanisms underlying the transition from a drug-sensitive to a drug-tolerant state still elude us. Here, we show that global chromatin reorganization is a recurrent and specific feature of KRAS-dependent cells that tolerated KRAS silencing. We show that KRAS-dependent cells undergo G0/G1 cell cycle arrest after KRAS silencing, presenting a transcriptomic signature of quiescence. Proteomic analysis showed upregulated chromatin-associated proteins and transcription-associated biological processes. Accordingly, these cells shifted euchromatin/heterochromatin states, gained topologically associating domains, and altered the nanoscale physical organization of chromatin, more precisely by downregulating chromatin packing domains, a feature associated with the induction of quiescence. In addition, they also accumulated transcriptional alterations over time leading to a diversification of biological processes, linking chromatin alterations to transcriptional performance. Overall, our observations pinpoint a novel molecular mechanism of tolerance to KRAS oncogenic loss driven not by specific gene alterations but by global reorganization of genomic information, in which cells transition chromatin domain structure towards a more quiescent state and gain transcriptional reprogramming capacity.
Keywords: KRAS inhibition; chromatin packing scaling; drug tolerance; therapy resistance.