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Proffered paper session - Basic science

3542 - KRAS mutant and RAS/BRAF wild type colorectal cancer cells exhibit differences in the rewiring of signal transduction that can impact on future therapeutic strategies


20 Oct 2018


Proffered paper session - Basic science


Tumour Site

Colon and Rectal Cancer


Alexandros Georgiou


Annals of Oncology (2018) 29 (suppl_8): viii1-viii13. 10.1093/annonc/mdy268


A. Georgiou1, A. Stewart2, P. Thavasu2, E.A. Coker2, S. Poelsterl2, B. Al-Lazikani2, D. Cunningham3, S. Whittaker2, U. Banerji4

Author affiliations

  • 1 Cancer Therapeutics, Institute of Cancer Research/ Royal Marsden NHS Foundation Trust, SM2 5NG - Sutton/GB
  • 2 Cancer Therapeutics, Institute of Cancer Research, SM2 5NG - Sutton/GB
  • 3 Medicine, Royal Marsden NHS Foundation Trust, SM2 5PT - Sutton/GB
  • 4 Drug Development Unit  , The Institute of Cancer Research/Royal Marsden NHS Foundation Trust, SM2 5PT - Sutton/GB


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Abstract 3542


KRAS mutant (KRAS MT) and RAS/BRAF wild type (RAS WT) colorectal cancer (CRC) responds differently to targeted agents. A better understanding of early effects on signal transduction following exposure to targeted agents may explain this and inform future therapeutic strategies.


A panel of 25 CRC cell lines (10 KRAS MT, 15 RAS WT) and 13 samples isolated from CRC patients’ (pt) serous effusions were used. Using a multiplex antibody-based platform, simultaneous changes in 60 phosphorylated (p) proteins were quantified following 1-hour exposure to clinically used concentrations of: gefitinib, PI3K inhibitor: pictilisib, AZD5363, everolimus, trametinib and vemurafenib. Statistical analysis included logistic regression, T tests and Spearman’s correlation.


Collectively pMEK was the most commonly upregulated protein in KRAS MT cell lines; 55% KRAS MT vs 18% RAS WT, a difference that was significant (P < 0.05) with pictilisib and gefitinib. Triplicate validation with pictilisib confirmed upregulation of pMEK, as well as pERK, pMSK, pGSK3α in KRAS MT but not RAS WT cell lines. KRAS MT cells had a higher mean pictilisib half maximal inhibitory concentration (P < 0.05), being highest in cells with the greatest pMEK rise. Validation with gefitinib confirmed consistent downregulation of pMEK, pMSK, pGSK3α/β, pPRAS40 and pS6 in sensitive RAS WT but not KRAS MT cells (P < 0.05), despite comparable decrease of pEGFR. Gefitinib sensitivity was related to the degree of downregulation of the aforementioned proteins. In 10 KRAS MT pt samples, pMEK upregulation was most commonly seen with pictilisib (38% of pts). As in cell lines, gefitinib led to upregulation of intracellular effectors in KRAS MT pt samples e.g. mTOR in 40% of pts. In RAS WT cells compensatory activation of receptor tyrosine kinases was the commonest rewiring feature, e.g. pFGFR1 upregulation with gefitinib in 40% of cell lines and 66% of pts.


There are significant differences in the rewiring of signal transduction between KRAS MT and RAS WT CRC cells exposed to clinically relevant concentrations of PI3K and EGFR inhibitors. These differences can help devise/refine future strategies to combine targeted agents in CRC.

Clinical trial identification

NCT00825110, CCR3085.

Legal entity responsible for the study

Royal Marsden NHS Foundation Trust.


Cancer Research UK.

Editorial Acknowledgement


All authors have declared no conflicts of interest.

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