Cancer drug pan-resistance: pumps, cancer stem cells, quiescence, epithelial to mesenchymal transition, blocked cell death pathways, persisters or what?

Abstract

Although chemotherapy of tumours has scored successes, drug resistance remains the major cause of death of cancer patients. Initial treatment often leaves residual disease, from which the tumour regrows. Eventually, most tumours become resistant to all available chemotherapy. I call this pan-resistance to distinguish it from multi-drug resistance, usually describing resistance caused by upregulation of drug transporters, such as P-glycoprotein. In this review, I discuss mechanisms proposed to explain both residual disease and pan-resistance. Although plausible explanations are at hand for residual disease, pan-resistance is still a mystery. My conclusion is that it is time for a major effort to solve this mystery using the new genetically modified mouse tumour models that produce real tumours resembling cancer in human patients.

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

“…In this study, cellular and molecular pharmacological data demonstrate that DLC-carborane compounds target cancer and primary GBM CSCs highly selectively and also that these agents exert a very significant pharmacological behavior while sparing normal cells. Based on the principle of the elimination of CSCs toward achieving patient long-term cure rates in the clinical setting [3,6,7], it is of significance that DLCcarborane compounds exert such remarkable effect on GBM CSC lines. The effect is most meaningfully demonstrated by the determined IC 50 values, which are markedly 18 lower than those calculated for normal cells (ca.…”

“…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].…”

Transient TNF regulates the self-renewing capacity of stem-like label-retaining cells in sphere and skin equivalent models of melanoma

“…Despite advances in melanoma research and drug development, 10-20% of clinically disease-free patients relapse 5-10 years following an initial treatment [1,2]. This phenomenon, which is known as tumor dormancy [3], has been related to the existence of therapy-resistant cells with stem-like activity [4][5][6]. Recent findings suggest that cancer stem cells, in response to chemotherapy, enter protective, prolonged, but reversible, quiescence [7] and remain dormant without causing any clinical manifestations until activated [8].…”

BRCA2-Deficient Sarcomatoid Mammary Tumors Exhibit Multidrug Resistance

“…A major clinical problem in cancer therapy is resistance of tumors to all available therapies, a phenomenon called panresistance (1). After an initial response primary tumors and especially metastases do not respond anymore to treatment, including radiotherapy.…”