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Genetic variants of kinases suppressors of ras in KRAS-BRAF wild-type metastatic colorectal cancer patients treated with cetuximab and irinotecan

conference contribution
posted on 2023-06-07, 07:59 authored by Leonor Benhaim, Fotios Loupakis, Wu Zhang, Armin Gerger, Pierre Oliver Bohanes, David Páez, Chiara Cremolini, Takeru Wakatsuki, Dongyun Yang, Yan Ning, Rita El-Khoueiry, Hua Zhang, Lisa Salvatore, Marta Schirripa, Alfredo Falcone, Georgios GiamasGeorgios Giamas, Justin Stebbing, Heinz-Josef Lenz
Background Scaffold proteins kinase suppressor of ras (KSRs) have emerged as critical modulators of the EGFR pathway that binds to RAS promoting ERK activation. KSR1 and KSR2 have been shown to be over expressed in various solid tumours including colon cancer. In-vitro, the down-regulation of KSR results in reduction of cells proliferation and tumour growth independently to KRAS status. Moving from this biological rational we investigated the correlation between functional polymorphisms in the KSR genes and clinical outcomes in patients with KRAS and BRAF wild-type mCRC treated with cetuximab and irinotecan. Methods Germline DNA was obtained from peripheral blood of patients with mCRC KRAS and BRAF wild- type resistant to irinotecan treated with a combination of cetuximab and irinotecan. Seven functionally relevant SNP were selected on the basis of public literature resources and databases, 4 in the KSR1 and 3 in the KSR2 genes and analyzed by PCR followed by direct sequencing. All candidate SNPs were evaluated for association with response rate, PFS and OS. Results A total of 66 patients were included.After a median follow-up of 13.3 months, median PFS and OS were 4.7 and 11.3 months respectively. Seventeen out of 66 patients (26%) achieved a RECIST response. In univariate analysis, KSR2 rs11068551 any G(AG/GG) genotype was significantly associated with shorter PFS compared to that of A/A carriers (median 3.5 vs. 7.4 months, HR=1.74 [95%CI: 1-3.04] p=0.049, log-rank test). This result remained significant in a multivariate model (HR=2.13 [95%CI: 1.15-3.95], p=0.017, log-rank test). None of the other tested SNPs were significantly associated with outcomes. Conclusions Beyond KRAS and BRAF, some proteins including KSR are involved in modulating the level of activation of the EGFR pathway. Our results show that the functionally relevant KSR2 rs11068551 could affect PFS in advanced mCRC patients treated with cetuximab and irinotecan. Preclinical studies to confirm and further explain these preliminary findings are ongoing.

History

Publication status

  • Published

Journal

Journal of Clinical Oncology

ISSN

0732-183X

Publisher

American Society of Clinical Oncology (ASCO)

Issue

15

Volume

30

Page range

3597-3597

Event name

2012 Annual Meeting of the American Society of Clinical Oncology

Event location

Chicago, Illinois

Event type

conference

Event date

June 01 - 05 2012

Department affiliated with

  • Biochemistry Publications

Full text available

  • No

Peer reviewed?

  • No

Legacy Posted Date

2023-01-12

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