383P - RAS/AKT pathway mutations as predictive biomarkers in patients with colorectal cancer treated with the exportin 1 (XPO1) inhibitor selinexor (SEL)...

Date 10 October 2016
Event ESMO 2016 Congress
Session Poster display
Topics Clinical research
Translational Research
Basic Scientific Principles
Basic Principles in the Management and Treatment (of cancer)
Presenter Valerie Heong
Citation Annals of Oncology (2016) 27 (6): 114-135. 10.1093/annonc/mdw368
Authors V.Y.M. Heong1, P. Koe1, W.P. Yong2, R. Soo3, C.E. Chee1, A. Wong2, Y.L. Thian2, R. Sundar4, J.S. Ho2, A. Gopinathan2, S.C. Lee2, B.C. Goh2, D.S. Tan2
  • 1Oncology, The Cancer Institute National University Hospital, 119074 - Singapore/SG
  • 2Haematology-oncology, National University Hospital, 119228 - Singapore/SG
  • 3Cancer Institute, National University Cancer Institute, Singapore, Singapore/SG
  • 4Medical Oncology, National University Cancer Institute, Singapore, 119228 - Singapore/SG

Abstract

Background

Localization of p27 within a cell determines its function. Cytoplasmic sequestration of p27 promotes oncogenic activity while its nuclear retention inhibits tumorigenesis. RAS activation in tumours indirectly causes cytoplasmic sequestration of p27 via the activation of its effectors PI3K/AKT and Raf1/MEK/ERK pathway. SEL is a potent XPO1inhibitor that forces nuclear retention of multiple proteins including p27 resulting in tumour cell death.

Methods

SEL was administered orally to patients with advanced solid cancers in a phase I dose escalation study. Response was evaluated every two cycles (RECIST v1.1). Nuclear-cytoplasmic localisation of p27 in RAS and/ or AKT pathway activated tumours from tumour biopsies pre and post SEL were determined together with nuclear retention of other XPO1 cargo proteins, proliferative and apoptotic markers.

Results

Outcomes of 18 advanced colorectal cancer (CRC) patients with known RAS and AKT pathway mutational status (12M/6F; median age 59.5; ECOG PS 0/1: 9/9), who received at least 8 weeks of SEL were analysed. 50% (n = 9) had an activating mutation in the RAS pathway (KRAS/NRAS/BRAF: 7/1/1); 16.7%(n = 3) in the PI3K/AKT pathway (PI3K/AKT/PTEN loss: 1/1/1); 11.1% (n = 2) in both and 44.4%(n = 8) did not harbour mutations in either (WT). Median PFS for patients with a mutation in either pathway compared to WT patients were 78 days vs 50days, respectively;(p value = 0.129). 40% (n = 4) CRC patients with RAS/AKT pathway mutation achieved a disease control rate (DCR) of > 3 mths compared to 12.5% of CRC WT patients. Analysis of pre and post SEL treated biopsy samples confirmed increased nuclear retention of p27 in the KRAS/AKT mutant tumours with DCR > 3mths.

Conclusions

RAS and AKT pathway activated CRC appear to have a longer PFS with an increased number of patients achieving DCR of >3 months compared to WT tumours. Cytoplasmic translocation of p27 could be a key oncogenic mechanism in RAS and/or AKT pathway activated tumours and can be targeted by inhibition of XPO1

Clinical trial identification

Legal entity responsible for the study

National University Hospital, Singapore

Funding

tudy support: Karyopharm Therapeutics Inc. and National Medical Research Council

Disclosure

D. Tan: Advisory board - Astra Zeneca. All other authors have declared no conflicts of interest.