Therapeutic targeting of nuclear export and import receptors in cancer and their potential in combination chemotherapy

Abstract

Systemic modalities are crucial in the management of disseminated malignancies and liquid tumours. However, patient responses and tolerability to treatment are generally poor and those that enter remission often return with refractory disease. Combination therapies provide a methodology to overcome chemoresistance mechanisms and address dose‐limiting toxicities. A deeper understanding of tumorigenic processes at the molecular level has brought a targeted therapy approach to the forefront of cancer research, and novel cancer biomarkers are being identified at a rapid rate, with some showing potential therapeutic benefits. The Karyopherin superfamily of proteins is soluble receptors that mediate nucleocytoplasmic shuttling of proteins and RNAs, and recently, nuclear transport receptors have been recognized as novel anticancer targets. Inhibitors against nuclear export have been approved for clinical use against certain cancer types, whereas inhibitors against nuclear import are in preclinical stages of investigation. Mechanistically, targeting nucleocytoplasmic shuttling has shown to abrogate oncogenic signalling and restore tumour suppressor functions through nuclear sequestration of relevant proteins and mRNAs. Hence, nuclear transport inhibitors display broad spectrum anticancer activity and harbour potential to engage in synergistic interactions with a wide array of cytotoxic agents and other targeted agents. This review is focussed on the most researched nuclear transport receptors in the context of cancer, XPO1 and KPNB1, and highlights how inhibitors targeting these receptors can enhance the therapeutic efficacy of standard of care therapies and novel targeted agents in a combination therapy approach. Furthermore, an updated review on the therapeutic targeting of lesser characterized karyopherin proteins is provided and resistance to clinically approved nuclear export inhibitors is discussed.

Relevant Aspects of Combined Protocols for Prevention of N(M)AFLD and Other Non‐Communicable Diseases

“…[73] Recently, tumorigenesis was associated with the dysregulation of cellular import, export or bidirectional transport receptors by changes in their expression or subcellular localization, [74] which provoke the nuclear retention of tumor suppressors and key mediators of oncogenic signaling. [75] Thus, nuclear transport inhibition (e.g., exportin 1 (EXPO1) by selinexor) combined with the anticancer drug dexamethasone, abolish oncogenic signaling and restore the activity of tumor suppressor functions, a combination therapy that may overcome chemoresistance and focus on dose-limiting toxicities. [75] Several preclinical studies have reported many combination agents for colon cancer prevention using different mice and rat models that moved into clinical trials.…”

“…[75] Thus, nuclear transport inhibition (e.g., exportin 1 (EXPO1) by selinexor) combined with the anticancer drug dexamethasone, abolish oncogenic signaling and restore the activity of tumor suppressor functions, a combination therapy that may overcome chemoresistance and focus on dose-limiting toxicities. [75] Several preclinical studies have reported many combination agents for colon cancer prevention using different mice and rat models that moved into clinical trials. [76] These comprise the assessment of the prevalence of T2DM in patients with colorectal adenocarcinoma (CRC) and survival for CRC in patients defined by CRC stage, presence or absence of T2DM treated with metformin, and presence or absence of daily aspirin therapy.…”