XPO1 inhibition can reverse hypoxia-induced resistance to bortezomib

Exportin 1 (XPO1) was identified as a target for Multiple Myeloma (MM) therapy, as increased levels have been found in MM cells. Barbara Muz and colleagues from the Department of Radiation Oncology, Cancer Biology Division, Washington University in Saint Louis School of Medicine, USA, investigated the use of an XPO1 inhibitor, selinexor (the selective inhibitor of nuclear export; SINE compound KPT-330), to target MM cells both in-vitro and in-vivo, and published their findings in the June edition of Translational Oncology. Selinexor was found to overcome hypoxia-induced drug resistance, decrease tumor burden and sensitize MM cells to bortezomib.

Key Highlights:

• Selinexor was found to inhibit survival and drive caspase-mediated apoptosis of myeloma (MM.1S) cells cultured in-vitro; the effect was more pronounced in hypoxic conditions
• Combining selinexor with bortezomib led to increased apoptosis compared to using bortezomib alone, and the effect was additive
• Selinexor was also effective as a single agent in-vivo:
  • Tumor initiation was significantly delayed and led to a diminished overall tumor burden compared to control-treated mice, significantly extending the survival time and limiting deterioration
  • Progression was delayed in an established MM mouse model and survival was significantly extended
• Selinexor combined with bortezomib delayed tumor growth in a bortezomib-resistant MM mouse model:
  • Tumor burden was 60% smaller than in mice treated with bortezomib alone
  • Survival was improved as 50% of mice treated with selinexor and bortezomib still alive at day 52 (p = 0.005); 100 % of mice treated with bortezomib alone had died by day 50

Hypoxia in the BM microenvironment has been shown to contribute to MM development and to enhance drug resistance. XPO1 up-regulation has been specifically linked to MM patients that exhibit bortezomib resistance. Therefore, combining proteasome inhibitors with XPO1 inhibition could overcome drug resistance and offer a new therapeutic option. The Phase 3 BOSTON trial to assess treatment of treatment relapsed or refractory MM patients with selinexor and bortezomib, led by researchers at Karyopharm Therapeutics, is currently underway. Planned enrolment is scheduled for completion in 2018, with a planned interim analysis expected in 2019.