Mechanisms of tumor cell resistance to the current targeted-therapy agents

Abstract

Resistance to chemotherapy agents is a major challenge infront of cancer patient treatment and researchers. It is known that several factors, such as multidrug resistance proteins and ATP-binding cassette families, are cell membrane transporters that can efflux several substrates such as chemotherapy agents from the cell cytoplasm. To reduce the adverse effects of chemotherapy agents, various targeted-based cancer therapy (TBCT) agents have been developed. TBCT has revolutionized cancer treatment, and several agents have shown more specific effects on tumor cells than chemotherapies. Small molecule inhibitors and monoclonal antibodies are specific agents that mostly target tumor cells but have low side effects on normal cells. Although these agents have been very useful for cancer treatment, however, the presence of natural and acquired resistance has blunted the advantages of targeted therapies. Therefore, development of new options might be necessary. A better understanding of tumor cell resistance mechanisms to current treatment agents may provide an appropriate platform for developing and improving new treatment modalities. Therefore, in this review, different mechanisms of tumor cell resistance to chemotherapy drugs and current targeted therapies have been described.

Hypoxia Induces Multidrug Resistance via Enhancement of Epidermal Growth Factor-Like Domain 7 Expression in Non-Small Lung Cancer Cells

“…The main underlying mechanisms of tumor MDR include: overexpression of ATP-binding cassette transporters, a blunted apoptosis pathway, enhanced DNA repair activity, increased metabolic activities, a loss of specific oncogenes, and a gain in stem cell plasticity [4,5,6]. Among these potential factors, ATP-binding cassette transporters are the most representative, and they are the mainstay of MDR reversion in clinical cancer chemotherapy [7,8]. For decades, several reversal agents have been applied in tumor MDR treatments, but they still show daunting therapeutic effects.…”

Evidence of a role for functional heterogeneity in multidrug resistance transporters in clinical trials of P‐glycoprotein modulation in acute myeloid leukemia

“…Five key calculations using mean fluorescence intensity (MFI) values allowed for cross comparisons between blast populations in the two bioassays. The calculations include (1) P-gp accumulation ratio, (2) P-gp efflux ratio, (3) percent unimpeded efflux for total MDR activity, (4) percent efflux in the presence of zosuquidar, and (5) percent inhibition of efflux by zosuquidar. The P-gp accumulation and P-gp efflux ratios identify only presence or absence of P-gp activity and are particularly important because they have been described and used in association with multiple zosuquidar AML clinical trials (23, 24, 26, 27, 31), including as a companion diagnostic (26).…”

Evolutionary scalpels for dissecting tumor ecosystems

“…A majority of patients treated with tyrosine kinase inhibitors alone develop mutations in the tyrosine kinase KIT conferring drug resistance 73 ; in fact, multiple different mutations often occur in a single patient, each within a separate lesion 74 . This observation suggests that the population of cells with drug-resistant KIT may be large and diverse in these patients prior to therapy.…”