Molecular chess? Hallmarks of anti-cancer drug resistance

Abstract

BackgroundThe development of resistance is a problem shared by both classical chemotherapy and targeted therapy. Patients may respond well at first, but relapse is inevitable for many cancer patients, despite many improvements in drugs and their use over the last 40 years.ReviewResistance to anti-cancer drugs can be acquired by several mechanisms within neoplastic cells, defined as (1) alteration of drug targets, (2) expression of drug pumps, (3) expression of detoxification mechanisms, (4) reduced susceptibility to apoptosis, (5) increased ability to repair DNA damage, and (6) altered proliferation. It is clear, however, that changes in stroma and tumour microenvironment, and local immunity can also contribute to the development of resistance. Cancer cells can and do use several of these mechanisms at one time, and there is considerable heterogeneity between tumours, necessitating an individualised approach to cancer treatment. As tumours are heterogeneous, positive selection of a drug-resistant population could help drive resistance, although acquired resistance cannot simply be viewed as overgrowth of a resistant cancer cell population. The development of such resistance mechanisms can be predicted from pre-existing genomic and proteomic profiles, and there are increasingly sophisticated methods to measure and then tackle these mechanisms in patients.ConclusionThe oncologist is now required to be at least one step ahead of the cancer, a process that can be likened to ‘molecular chess’. Thus, as well as an increasing role for predictive biomarkers to clinically stratify patients, it is becoming clear that personalised strategies are required to obtain best results.

Sequential combinations of chemotherapeutic agents with BH3 mimetics to treat rhabdomyosarcoma and avoid resistance

“…As mentioned above, one of the hallmarks of cancer is treatment adaptation and resistance to anti-cancer drugs 23 . This resistance can be acquired by different mechanisms such as drug target alterations (mutations), drug export transporters' gain, increased DNA damage repair, altered proliferation and, as we further investigated, through anti-apoptotic BCL-2 proteins 26 .…”

In Vitro Toxicity of Asparagus Saponins in Distinct Multidrug‐Resistant Colon Cancer Cells

“…[35] To the best of our knowledge, we demonstrated for the first time that PD and other furostanol saponin, HTSAP-10, with high cytotoxic activity against colon cancer cells, were obtained from HT asparagus. Of note, we have previously published that these saponins are resistant to simulated digestion [19] and due to their poor intestinal absorption, [36] they are colonaccessible, where they may exert their biological effects. This represent an advantage respect to 5-FU that suffers a reduction of cellular drug uptake because water-soluble drugs may attach to transporters carrying nutrients and therefore fail to accumulate in the colonic tumoral cells at relevant concentrations.…”

Targeting P‐glycoprotein and SORCIN: Dihydromyricetin strengthens anti‐proliferative efficiency of adriamycin via MAPK/ERK and Ca2+‐mediated apoptosis pathways in MCF‐7/ADR and K562/ADR

“…According to a previous report, approximately 40% of human tumors develop MDR and patients with MDR performed poor outcome (Higgins, ). In the last 40 years several mechanisms of MDR have been described such as changes in drug targets, overexpression of efflux drug transporters, reduced susceptibility to apoptosis, decreased DNA damage, etc (Cree & Charlton, ; Gottesman, Lavi, Hall, & Gillet, ; Palmeira, Sousa, Vasconcelos, & Pinto, ). Of all the mechanisms in MDR, over expression of ATP‐binding cassette (ABC) transporters, a family of efflux drug transporters, is the most widely and deeply recognized mechanism.…”