Toward a Better Understanding of the Complexity of Cancer Drug Resistance

Abstract

Resistance to anticancer drugs is a complex process that results from alterations in drug targets; development of alternative pathways for growth activation; changes in cellular pharmacology, including increased drug efflux; regulatory changes that alter differentiation pathways or pathways for response to environmental adversity; and/or changes in the local physiology of the cancer, such as blood supply, tissue hydrodynamics, behavior of neighboring cells, and immune system response. All of these specific mechanisms are facilitated by the intrinsic hallmarks of cancer, such as tumor cell heterogeneity, redundancy of growth-promoting pathways, increased mutation rate and/or epigenetic alterations, and the dynamic variation of tumor behavior in time and space. Understanding the relative contribution of each of these factors is further complicated by the lack of adequate in vitro models that mimic clinical cancers. Several strategies to use current knowledge of drug resistance to improve treatment of cancer are suggested.

Pharmacological Development of Target-Specific Delocalized Lipophilic Cation-Functionalized Carboranes for Cancer Therapy

“…Moreover, the observation that the tested DLC-functionalized carboranes exhibit selective cytotoxicity towards primary GBM CSCs indicates their potential to drive cytotoxic actions to heterogeneous tumor cell subpopulations. This is an issue of some significance since such genetically-and molecularly-diverse cell types crucially restricts the therapeutics outcome and correlates with the emergence of cancer drug resistance [8]. Notably, following their pretreatment with DLC-carboranes, only normal cells were seen to recapitulate their full proliferation potential in media that were free from these compounds; this effect was verified through dilution assays.…”

“…The 96 well-plate was covered with aluminum foil and agitated for 15 min in a plate 8 shaker before quantification by spectrophotometry (plate reader, 570 nm). Cell-free wells provided the controls for each compound and medium [24]; results, from at least two independent experiments, are expressed as percentage cell growth relative to that determined for corresponding untreated control cultures.…”

“…It has been suggested that as long as technological advancements empower the translational medicine capacity in enabling the pharmacological exploitation of cancer cell molecular and genomic knowledge, the advances to therapeutically overcome heterogeneity and to target the tumor cell microenvironment will occur at increasing rates [2][3][4][5][6][7][8][9][10]. A major milestone towards organelle-specific drug delivery was reached by the discovery of delocalized lipophilic cations (DLCs) [11].…”

Therapeutic Potential of PI3K/Akt/mTOR Signalling Pathway: Effective Combination Therapy for Cancer

“…The recent advances in targeted immunotherapies and cytotoxic chemotherapy have led to an improved survival rate [3] . However till date the treatment of cancer is a major challenge for the reasons associated with the complexity of cell signalling pathways, heterogeneity of tumor cell, development of resistance to current therapy [4] and inevitable side effects [5] . Hence a need for the development of newer and more effective therapies to treat cancer and reduce side effects continues to exist.…”

Fighting tubulin-targeting anticancer drug toxicity and resistance

“…Unfortunately, resistance to AMCDs is commonly seen in a wide variety of cancer patients, significantly reducing their clinical response (Gottesman et al 2016). Resistance to AMCDs can be native, i.e.…”