Study authors found sequential treatment of Exportin 1 (XPO1) inhibitors followed by ataxia telangiectasia and Rad3-related (ATR) inhibitors resulted in significantly greater tumor growth inhibition in TP53-mutated colorectal cancerous cells, according to findings published in the Gastroenterology journal.

XPO1 is a major exporter that transports proteins and RNAs from the nucleus to the cytoplasm. XPO1 upregulation results in dysregulation of cargo proteins in both the nuclear and cytoplasmic compartments and has been identified in several other cancers. It was observed that XPO1 overexpression correlated with poor prognosis in colorectal cancer. KPT-330 (selinexor) and KPT-8602 (eltanexor) are both potent XPO1 inhibitors that cause apoptosis upon accumulation of cargo proteins in the nucleus.

Investigators systematically combined functional genomics of patient-derived tumor cells and xenografts (PDX) with in vitro high-throughput drug screens. They used a short hairpin RNA library to target 196 genes known to encode drug targets and conducted screens in 4 colorectal cancer PDX models.


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Authors then performed a high-throughput screening of drugs and classified tumor model responses to these drugs into the following 4 groups, based on the extension of the area under the curve (AUCn): Class 1 (AUCn>0.7), Class 2 (AUCn>0.4), Class 3 (AUCn>0.1), and Class 4 (AUCn<0.1).

KPT-8602 (eltanexor) was chosen to be used in treatment due to its diminished blood-brain barrier penetration, thus causing fewer side effects that might limit treatment at effective doses otherwise. KPT-8602 dosed 15 mg/kg on a 5 days on/2 days off schedule for 2 weeks was given to mice with TP53-mutant colorectal tumor cells. This dosing demonstrated strong tumor growth inhibition. However, it was noted that the mice also experienced >15% body weight loss. Lowered doses of 5 mg/kg and 10 mg/kg were better-tolerated and resulted in superior tumor growth inhibition, compared with 5-fluorouracil with negligible weight loss.

Sequential therapy combinations were also studied in vivo and the results were promising for this treatment approach. Combination treatment of KPT-8602 followed by ATR inhibitor AZD-6738 or palbociclib demonstrated tumor growth inhibition that was comparable to prolonged KPT-8602 monotherapy and was superior to both AZD-6738 monotherapy and palbociclib monotherapy. However, the reverse therapy sequence was inferior when AZD-6738 was given before KPT-8602. Investigators noted the combined therapies were associated with improved tolerability.

“Taken together, our findings suggest that administration of XPO1 inhibitors, especially in combination with ATR inhibitors, may be a novel therapeutic approach to treat patients with colorectal cancer. This mechanism-based combination strategy may prevent treatment adaptation to produce more durable responses in patients with this disease,” study authors concluded.

Reference

Inoue A, Robinson FS, Minelli R, et al. Sequential administration of XPO1 and ATR inhibitors enhances therapeutic response in TP53-mutated colorectal cancer. Gastroenterol. Published online March 18, 2021. doi: 10.1053/j.gastro.2021.03.022