Page 49 - Read Online

Page 148 Sendino et al. Cancer Drug Resist 2018;1:139-63 I http://dx.doi.org/10.20517/cdr.2018.09

It is still unclear why XPO1 E571 mutations are particularly common in certain types of cancer, and why
they may have different prognostic significance in different types of hematological malignancies. In fact,
the molecular mechanisms that may be responsible for the pathogenic effect of XPO1 mutations remain to
be established. Consistent with the location of the mutational “hotspot” proximal to the NES-binding site
[Figure 2B], it has been reported that the E571K mutation subtly increases the affinity of the receptor for
[32]
some NESs with a negatively charged carboxy-terminal end . Conceivably, this could lead to altered ex-
port of one or more cargos, whose mislocalization might in turn contribute to tumorigenesis.

Given its frequent alteration in human tumors, and its crucial cellular roles described above, XPO1 has
long been regarded as a potentially relevant target in cancer therapy.

XPO1 INHIBITION IN CANCER THERAPY
Development and preclinical evaluation of selective inhibitors of nuclear export
Even before XPO1 was identified as its cellular target, LMB (also called elactocin) had been found to pos-
[128]
sess antitumor activity, and it had been tested in a clinical trial .

LMB was found to have severe toxicities when administered to patients, precluding its development as a
[128]
clinically useful drug . Nevertheless, the availability of this potent and specific inhibitor made it possible
to carry out proof-of-concept experiments testing the effect of XPO1 inhibition in different tumor settings.
As an illustrative example, we will briefly describe some early data regarding the effect of LMB treatment
in chronic myelogenous leukemia (CML) cells expressing the BCR-ABL oncoprotein. Shortly after the
identification of XPO1 as a nuclear export receptor, the c-ABL kinase was identified as one of its cargos,
[77]
bearing a C-terminal NES that is also present in the BCR-ABL fusion protein . At that time, treatment
of BCR-ABL-positive CML patients was undergoing a dramatic improvement with the introduction of the
kinase inhibitor imatinib [129,130] . In this context, it was reported that the sequential combination of imatinib
plus LMB led to the nuclear entrapment of BCR-ABL, which selectively induced apoptosis of CML cells [131] .
Furthermore, subsequent experiments showed that the combination with LMB could overcome imatinib
[132]
resistance due to BCR-ABL amplification .

[7]
These and other encouraging findings in different tumor types (reviewed by Turner and Sullivan ) sug-
gested that XPO1 inhibition might represent a valid strategy for cancer treatment, fostering the search for
other XPO1 inhibitors. Over the next years, several natural and synthetic inhibitors of XPO1 were reported
[10]
[133]
(reviewed by Tan et al. and Senapedis et al. ). Similar to LMB, these compounds bind covalently to
XPO1 residue C528, and occupy the NES-binding groove, blocking access to NESs. However, unlike LMB,
some of these novel inhibitors, such as CBS9106 or S109, bind to XPO1 in a reversible manner, which was
associated to less severe toxicity in preclinical in vivo models [84,134] . Studies with these compounds further
validated XPO1 inhibition as a relevant strategy for cancer treatment. For example, blocking nuclear ex-
port of topoisomerase II with the XPO1 inhibitor Ratjadone C was found to sensitize multiple myeloma
[135]
(MM) cells to doxorubicin and etoposide .
While most XPO1 inhibitors have only been tested in vitro or in mouse xenograft, there is a series of com-
pounds, termed selective inhibitors of nuclear export (SINEs) that are undergoing development as po-
[133]
tential anticancer drugs, and some of these compounds are already being evaluated in clinical trials .

SINEs were developed in 2012 using structure-assisted relationship methodology combined with a novel
computational approach termed consensus-induced fit docking [136,137] , a strategy that relied crucially on the
recently solved structures of NES-bound XPO1. The “first-generation” series of SINEs included a relative
large number of slowly reversible XPO1 inhibitors, such as KPT-127, KPT-185, KPT-205, KPT-227, KPT-