Resistance to chemotherapy and molecular targeted therapies is a major problem facing current cancer treatment. Mechanisms of resistance to 'classical' cytotoxic chemotherapeutics and specific molecular targeted therapeutics share many features, such as activation of alternate pathways, activation of pro-survival pathways, expression of drug efflux transporters, or an increase in somatic mutations even from the same tissue of origin. However in different cancer types acquired drug resistance is not dependent on somatic mutations or drug efflux suggestive of an alternative mechanism like epigenetic changes and chromatin remodelling. Recent studies also suggest drug holidays after initial treatment with a drug re-sensitize cancer cells to the same drug.
Our preliminary data suggest that cancer cells exposed to various stress inducing conditions including drug exposure exert a common stress induced response characterized by chromatin remodelling and expression of specific markers like CD271. Cells surviving the initial stress induced response were termed induced drug tolerant cells (IDTCs). Specifically we found that transcriptional active histone marks like H3K4me3 and repressive marks like- H3K9Me3 and H3K27me3 are altered in IDTCs compared to parental cancer cells. These data were consistent in four different cancer cell lines ( lung, colon, breast and liver cancer) other than melanoma with different chemotherapeutics and molecular targeted therapies which indicates that this effect is neither a consequence for a specific therapy nor for a particular cancer rather a common mechanism of initial drug resistance. Along with that, different pro-survival pathways like pERK, pAKT, pMEK and pAMPK are also altered in different cancer cell lines.
Histone modifications, chromatin remodelling, and DNA methylation act in cohort to maintain the euchromatin and heterochromatin state of IDTCs. We aim to further elucidate target genes of active and inactive histone modifiers in IDTCs and in the transition of early- to acquired permanent drug resistance.