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Proffered paper session - Basic science

4599 - Receptor Tyrosine Kinase dependent PI3K activation is an escape mechanism to vertical suppression of the EGFR/RAS/MAPK pathway in KRAS-mutated colorectal cancer cell lines.

Date

20 Oct 2018

Session

Proffered paper session - Basic science

Topics

Colon and Rectal Cancer

Presenters

Pietro Paolo Vitiello

Citation

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

Authors

P.P. Vitiello1, C. Cardone1, D. Ciardiello1, G. Barra1, N. Matrone1, V. Belli1, G. Martini2, L. Poliero1, C. Borrelli1, M. Terminiello1, T. Troiani1, F. Morgillo1, F. Ciardiello1, E. Martinelli1

Author affiliations

  • 1 Medicina Di Precisione, Università degli Studi della Campania Luigi Vanvitelli, 80131 - Napoli/IT
  • 2 Centro Cellex, Vall D'Hebron institute of oncology (VHIO), 08035 - Barcelona/ES
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Abstract 4599

Background

Previous studies showed that the combination of an anti-Epidermal growth factor receptor (EGFR) and a MEK-inhibitor is active in KRAS-wild type colorectal cancers (CRCs) and reverts anti-EGFR primary resistance in KRAS mutated colorectal cancer cell lines. However, resistance onset is a limit to combination therapies.

Methods

We generated four different KRAS mutated CRC cell lines (HCT15, HCT116, LoVo, SW480) resistant to a combination of cetuximab (anti-EGFR antibody) and refametinib (BAY86-9766, selective MEK-inhibitor) after continuous exposure to increasing concentration of the drugs. Resistant clones had an IC50 20-100-fold higher than the parental cells. We evaluated by Western Blot (WB) analysis and quantitative Reverse Transcriptase Polymerase Chain Reaction (qRT-PCR) the expression and activation status of a panel of receptor tyrosine kinases (RTKs) and intracellular transducers. We further analysed by MTT assay the sensitivity of the cetuximab-MEKi resistant (CM-res) cell lines to different kinase knockdown or pharmacologic inhibition. Oncomine comprehensive assay analyses was used for identify new genetic alteration.

Results

We found consistent hyperactivation of the PI3K-AKT pathway coupled to the activation of multiple RTKs such as HER2, HER3 and IGF1R in resistant cells when compared to parental cells. Resistant clones exhibit an epithelial phenotype, more pronounced for mesenchymal-like parental cell lines of the CMS4 cluster (HCT116 and SW480). Either selective knockdown of these RTKs or treatment with the pan-HER inhibitor afatinib (BIBW2992) failed to revert the resistance phenotype in our cellular model, while treatment with pictilisib (GDC-0941, selective PI3Kα inhibitor) was able to restore the sensitivity to the drug combination. No new genetic alteration was detected.

Conclusions

Our in vitro preliminary data demonstrate that PI3K activation plays a central role in the acquired resistance to the combination of anti-EGFR and MEK-i in KRAS mutated colorectal cancer cell lines. PI3K activation is achieved through concurrent activation of multiple RTKs such as HER2, HER3 and IGF1R, suggesting a cooperative mechanism.

Clinical trial identification

Legal entity responsible for the study

Department of Precision Medicine - Università della Campania Luigi Vanvitelli.

Funding

Università della Campania Luigi Vanvitelli; Associazione Italiana Ricerca sul Cancro (AIRC).

Editorial Acknowledgement

Disclosure

All authors have declared no conflicts of interest.

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