Understanding Tumor Drug Tolerance and Resistance

Our research team is involved in understanding the diverse molecular mechanisms or adaptations of tumor cells contributing to drug tolerance and resistance. In this regard, the following aspects are investigated:

            1. Characterizing signaling and epigenetic adaptations of tumor cells upon drug stress: A toxic drug pressure often results in survival of a very small population of transitorily non-dividing tumor cells that eventually attain proliferative potential to re-populate the tumor. Our research is devoted towards understanding the signalling and epigenetic signatures of these 'tolerant cells' that serve as a pool of resilient cells re-establishing tumor population. We also compare the molecular responses after exposure to a toxic or a sub-toxic chemotherapeutic pressure. In this context, we have taken a next generation sequencing based approach followed up by extensive in silico analysis, and wet lab validations towards identification of druggable targets. Herein, we have observed dynamic alteration in developmentally relevant signaling pathways and modification of histone marks upon drug stress. Their functional implications are investigated. Overall, the understanding of the adaptive strategies of tumor cells upon drug pressure is directed towards identification of probable therapeutic targets preventing drug tolerance, resistance and hence associated recurrence of cancer.

          2. Understanding the role of autophagy during drug stress: The cellular homeostatic process, autophagy has often been implicated in hindering drug sensitivity. However, the precise mechanism- of regulation of autophagy and the latter itself controlling cellular survival under drug pressure is poorly understood. Herein, we monitor autophagy after differential drug pressure in tumor cells. Thereafter, coupled with in silico analysis we identify signaling molecules/proteins regulating or having a crosstalk with autophagy. We further explore how modulating the identified molecules/autophagy can enhance chemotherapeutic sensitivity. In this context, we are further interested to explore the role of selective autophagy-mitophagy upon drug stress.

        3. Exploring the role of master transcription regulator- YAP in drug resistance: Alteration in expression of developmentally active signaling pathways is a hallmark of cancer and associated drug resistance. In this regard, the dys-regulation of Hippo signaling pathway is often associated with cancer. Currently we are exploring the role of Hippo signaling pathway components, like YAP under drug stress and its crosstalk with cellular adaptive strategies. The differential localization of YAP and target genes under its control upon drug pressure is investigated.

                4. Analyzing role of high glucose in tumor drug resistance: Hyperglycemic conditions are often positively correlated with progression of cancer, say pancreatic cancer. Especially, hyperglycemia is known to be associated with drug resistance as well. However, the precise mechanism of how hyperglycemia has an impact on drug resistance is poorly characterized. In this project, we explore alteration in expression of long non-coding RNAs (lncRNAs) with high glucose and explore its role in drug resistance. From in silico analysis and wet lab validation we have shortlisted a set of lncRNAs that are dys-regulated under hyperglycemic conditions in pancreatic cancer cells. Through genetic manipulation, their role in resistance is thereafter investigated. Moving ahead, we explore whether these lncRNAs regulate chromatin dynamics under high glucose conditions thus controlling selective transcription of genes.

          5. Role of GOF p53 in drug resistance: p53 is one of the most important tumor suppressors; however, in over half of human cancers, p53 is inactivated due to mutations. Mutant p53 possess distinctive activities of their own, often not present in the wild-type p53 protein. This endows the mutant proteins with activities that contribute to tumor progression and chemo-resistance. However, the mechanism by which these mutant cancer cells can be sensitized has not been extensively studied. In this project, we explore the potential of regulation of protein homeostasis as a therapeutic strategy to attenuate GOF-p53 mediated effect on drug resistance and survival    

6. Nanoparticles based therapeutic strategy for drug resistance: Traditional cancer therapy uses highly cytotoxic drugs as chemotherapy. To reduce the off-target toxicity nanotechnology based platforms have emerged as attractive tools in cancer therapy. The nanoparticles (NPs) can home into the tumor efficiently by using unique leaky vasculature (EPR effect). Inspired by the need of developing novel biocompatible and biodegradable nano-platform, in collaboration with other groups we are analyzing nanoparticulate compounds as drugs.

7. Platelet autophagy and thrombosis: This project explores the role of autophagy and selective autophagy like, mitophagy in low oxygen induced platelet activation and thrombosis. This project is remotely associated with cancer. Rather the objective of this project is directed towards reducing and designing an appropriate therapy to prevent hypoxia induced thrombosis in people moving to high altitudes, especially, the soldiers.