Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Ravindran Menon, D.
A model Integrating Acquired Drug Resistance in Cancer
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medical University of Graz; 2014. pp. 93
[OPEN ACCESS]
FullText
- Autor*innen der Med Uni Graz:
- Ravindran Menon Dinoop
- Betreuer*innen:
- Schaider Helmut
- Wolf Peter
- Altmetrics:
- Abstract:
- Acquired drug resistance is a major challenge for the successful treatment of any cancer. Even with the advent of molecular targeted therapy adding to the already existing therapies the occurrence of resistance still prevailed. The key and obvious primary reason for the phenomenon of acquired drug resistance is that the cells are surviving the initial hit by the drug. Various reasons have been incriminated to allow for the survival of residual cells after treatments. These include extrinsic factors like growth factors and cytokines in the tumour microenvironment or which are secreted by the cancer cells themselves. Intrinsic factors also have been attributed to be important which include the activation of alternative pathways seen to be a natural response to inhibition or targeting of cancer driving genes. Another aspect of intrinsic factors responsible for acquired drug resistance is the presence of multiple drug tolerant stem like cells which are reported to be enriched in the residual population. So far the existing literature has delineated divergent mechanisms contributing to multiple drug resistance in this population including drug efflux mechanisms and chromatin modifications. However, the underlying cause for the occurrence of a multiple drug resistant cancer stem cell like population has been quite obscure as the only explanation that has been given so far is that they pre-exist in the parent population. It also needs to be determined whether there is a link between intrinsic and extrinsic factors. Hence this study aimed at tackling these questions using a BRAF mutant melanoma model for which BRAF and MEK inhibitors have currently been developed as a primary treatment strategy. In the course of these studies the response of melanoma cells to BRAF and MEK inhibitors was observed to be largely affected by the presence of growth factors and cytokines like TGF-ß1 and TNF-a. The regulation of Twist1, an anti-apoptotic protein, through these pathways seems to determine the number of residual cells surviving the drug exposure. Cells surviving after 12 days of drug exposure were observed to be always multiple drug tolerant irrespective of the condition and drug they were exposed to. In an effort to characterize the reasons behind that I observed that cancer cells have a time dependent general intrinsic capability to exhibit an innate primary response to adverse environmental conditions like hypoxia or low glucose, but which is also triggered by drug exposure. This response induces a multiple drug tolerant stem like state in the cancer cells which drives the process of acquired drug resistance. The multiple drug tolerant state was characterised by the induction of stem cell markers like CD271, ABCB5 and increased ALDH activity along with global chromatin remodelling. Moreover the cells at that state exert a higher angiogenic potential making the population highly tumorigenic. These multiple drug tolerant cells are also characterized by the activation of multiple signalling cascades that contribute to highly active AKT and ERK survival pathways making them even more difficult to be targeted. So it seems that the micro-environmental conditions that exist at the time of exposure to drugs, including the presence of growth factors and cytokines, determine which percentage of cells might survive the initial drug exposure exhibiting an innate adaptive response to gain multiple drug tolerant properties. Together my studies point to a unifying model of acquired drug resistance, which could be used to significantly improve the administration of anticancer treatment regimens eventually leading to a sustainable disease.