Role of DNA Damage and Repair Pathway in Chemo & Radio Resistance

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Cell experiences several different types of DNA damage by both endogenous and exogenous factors. Faithful maintenance of the genome integrity is crucial for its survival. Majority of the cancer therapeutics exploits the same by inducing DNA damage to an extent that cell undergoes death. However, the degree of DNA repair mechanisms involved in different cases; either an individual or therapeutic regimen varies. The efficiency of repair mechanisms renders resistance to the cancer cell. Cancer cells could be innately resistant to the therapy or acquire resistance during the course of therapy. We in the lab are trying to understand the regulation of DNA damage repair (DDR) at different stages of treatment of Glioblastoma (GBM) and Acute Myeloid Leukemia (AML).

AML therapy resistance is an outcome of deregulation of multiple biological processes such as DNA damage repair pathway. To understand the mechanism of the DDR pathway mediated resistance, our lab established an in-vitro cellular model of acquired resistance of leukemia. Using this model, we reported that regulation of DNA repair acquired by an initial drug-tolerant state (or early drug-resistant state-EDRP) is different from that of late drug-resistant state (LDRP) (Salunkhe et.al., IJC 2018). Currently, we are trying to delve into the depth of those mechanisms which render chemoresistance in these EDRP and LDRP cells.

We had also reported radiation-induced multinucleated giant cells (MNGCs) formation as a primary cause of resistance & relapse in GBM (Kaur et.al., Carcinogenesis 2015). MNGCs are non-proliferative in nature and undergo therapy induced cellular senescence (TICS) with persistent DNA damage response (DDR). However, interestingly, they escape from senescence and recur as highly invasive & migratory mononucleated relapse GBM. We have identified functional interplay between DNA repair pathways and epigenetic modifications that impart resistance to residual cells (Kaur et al., Neuro Oncology 2020; Ghorai A et al., Cancer Letters 2020). We are now further delineating the molecular details of this link between chromatin and DNA damage repair in the context of radio-chemo resistance. Furthermore, we are also trying to understand how MNGCs reverse TICS with particular focus on three aspects, a) Role of PARP-1 in TICS, b) Role of replication stress in the manifestation of TICS, where detailed dynamics of replication factories are being studied, and c) Telomere biology in TICS, where telomere dysfunction is being assessed to understand TICS.