Abstract C005: TP53 wildtype status can predict sensitivity to XPO1 inhibitors in Patient-Derived Cancer Models
Authors: Maloof Marie , Ellero Andrea , Taverna Pietro , Walker Christopher J 
Published: December 2023

Abstract
Introduction: Selinexor (SEL) and eltanexor (ELT) are selective inhibitors of exportin 1 (XPO1), that lead to the nuclear accumulation and activation of key tumor suppressors (e.g. p53, p21, RB, and FOXO), resulting in selective cancer cell death. In the SIENDO trial of SEL maintenance for patients with advanced stage or relapsed endometrial cancer (EC), SEL reduced disease progression compared to placebo, with a more pronounced reduction seen in patients with TP53 wild-type (WT) EC (Makker et al, ASCO 2022). As TP53 is the most commonly mutated gene in human cancers, and p53 is a cargo of XPO1, we investigated whether TP53 wild type (WT) status could serve as a mechanistic predictor for cancer cell sensitivity to XPO1 inhibitors.
Methods: PDO and PDX models representing 17 cancer types, each with duplicate TP53 WT and MUT models were used (4 models per cancer type), with an emphasis on models with common hotspot MUTs. Tumor types were included if biological replicate models with TP53 wild-type or TP53 mutations were available for comparison. SEL, ELT and a control agent (CDDP or staurosporine) IC50 values after 5 days of exposure were calculated using CellTiter Glo assay. Sensitivity to SEL and ELT was considered TP53 WT dependent for each cancer type if the IC50 values for the TP53 MUT models were at least 1.5x higher than the average IC50 for the TP53 WT models. Similarly, the IC50 of SEL at 72h was determined for HCT116 WT and R175H cells to directly evaluate the association between TP53 MUT and resistance to XPO1 inhibitors in a syngeneic background.
Results: In PDX/PDO models, sensitivity to SEL and/or ELT was determined to be TP53 WT dependent in 9 cancer types (endometrial, ovarian, kidney, liver, esophageal, lung adeno and squamous, pancreatic, and bladder). For example, the 2 TP53 WT EC PDX tested were ~20 fold more sensitive to SEL and ELT than 2 EC PDX with mutations within the TP53 DNA binding domain (TP53 WT SEL IC50 = 31nM and 61nM; p.Y220C SEL IC50= 333nM; p.R213* SEL IC50 = 1542nM). Interestingly, the IC50 of SEL and ELT were lower than CDDP for the TP53 WT EC models, as well as in the kidney cancer models. For the remaining 8 indications (head and neck, gastric​, gallbladder​, cholangiocarcinoma, cervical​, breast​, mixed mullerian​, prostate​​), XPO1 inhibitor sensitivity was TP53 WT independent. Reduced sensitivity to SEL was also observed in syngeneic HCT116 cells with the TP53 R175H (IC50=343 nM) MUT compared to WT (IC50=174 nM). Notably, TP53 MUT status conferred resistance to the control agents in only models of two cancer types (esophageal and lung adenocarcinoma), demonstrating specificity between TP53 MUT status and XPO1 inhibitors.
Conclusions: Using TP53 WT status as a biomarker of sensitivity to XPO1 inhibitors SEL and ELT is cancer-type specific. Further experiments are ongoing to validate these findings in CRISPR-engineered SNG-M EC cells with clinically relevant R175H and R248Q TP53 hotspot mutations, including experiments related to cancer-type specific SEL/ELT mechanism of action.
Citation Format: Marie Maloof, Andrea Ellero, Pietro Taverna, Christopher J Walker. TP53 wildtype status can predict sensitivity to XPO1 inhibitors in Patient-Derived Cancer Models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C005.