Search

ABCB5 is a member of the ABC transporter superfamily composed of 48 transporters, which have been extensively studied for their role in cancer multidrug resistance and, more recently, in tumorigenesis. ABCB5 has been identified as a marker of skin progenitor cells, melanoma, and limbal stem cells. It has also been associated with multidrug resistance in several cancers. The unique feature of ABCB5 is that it exists as both a full transporter (ABCB5FL) and a half transporter (ABCB5β). Several studies have shown that the ABCB5β homodimer does not confer multidrug resistance, in contrast to ABCB5FL. In this study, using three complementary techniques; (1) nanoluciferase-based bioluminescence resonance energy transfer, (2) co-immunoprecipitation, and (3) proximity ligation assay, we identified two novel heterodimers in melanoma: ABCB5β/B6 and ABCB5β/B9. Both heterodimers could be expressed in high-five insect cells and ATPase assays revealed that they have a basal ATPase activity. These results are an important step toward untangling the functional role of ABCB5β in melanocytes and melanoma.

Cancer develops resistance to treatments through many mechanisms. Single-cell analyses reveal the intratumor heterogeneity and dynamic relationships between cancer cell subpopulations. These analyses also highlight that various mechanisms of resistance may coexist in a given tumor. Studies have unraveled how the microenvironment affects tumor response to treatments and how cancer cells may adapt to these treatments. Though challenging, individualized treatment based on the molecular characterization of the tumor should become the new standard of care. In the meantime, the success rate of clinical trials in oncology remains dramatically low. There is a need to do better and improve the predictability of preclinical models. This requires innovative changes in ex vivo models and the culture system currently being used. An innovative ligand design is also urgently needed. The limited arsenal of medicinal chemistry reactions and the biases of scaffold selection favor structurally similar compounds with linear shapes at the expense of disc and spherical shapes, which leave a large chemical shape space untouched. In this regard, venoms have received increasing interest as a wellspring for drug candidates. Overall, the characterization of tumor heterogeneity has contributed to advancing our understanding of the mechanisms that underlie cancer resistance to treatments. Targeting these mechanisms will require setting key milestones to significantly improve the translatability of preclinical studies to the clinic with the hope of increasing the success rate of clinical trials.

Members of the ATP binding cassette (ABC) transporter family perform a critical function in maintaining lipid homeostasis in cells as well as the transport of drugs. In this review, we provide an update on the ABCG-transporter subfamily member proteins, which include the homodimers ABCG1, ABCG2 and ABCG4 as well as the heterodimeric complex formed between ABCG5 and ABCG8. This review focusses on progress made in this field of research with respect to their function in health and disease and the recognised transporter substrates. We also provide an update on post-translational regulation, including by transporter substrates, and well as the involvement of microRNA as regulators of transporter expression and activity. In addition, we describe progress made in identifying structural elements that have been recognised as important for transport activity. We furthermore discuss the role of lipids such as cholesterol on the transport function of ABCG2, traditionally thought of as a drug transporter, and provide a model of potential cholesterol binding sites for ABCG2.