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75P - Role of p21-activated kinase (PAK) in K-RAS mutant human colorectal cancer models

Presentation Number
75P
Lecture Time
17:10 - 17:10
Speakers
  • Roberta C. Orsini (Napoli, IT)
Session Name
Location
Foyer La Scene, Paris Marriott Rive Gauche, Paris, France
Date
05.03.2018
Time
17:10 - 18:00
Authors
  • Roberta C. Orsini (Napoli, IT)
  • Valentina D'Amato (Napoli, IT)
  • Roberta Rosa (Napoli, IT)
  • Concetta Di Mauro (Napoli, IT)
  • Paola Ciciola (Napoli, IT)
  • Alberto Servetto (Napoli, IT)
  • Fabiana Napolitano (Napoli, IT)
  • Roberta Marciano (Napoli, IT)
  • Sabino De Placido (Napoli, IT)
  • Roberto Bianco (Napoli, IT)

Abstract

Background

RAS mutations promote resistance to anti-EGFR targeted agents in colorectal cancers (CRCs) by disabling RAS intrinsic GTPase activity, therefore increasing an EGFR-independent activation of PI3K/AKT and MAPK pathways. However, up to 25% of CRC patients are refractory to EGFR inhibitors even in absence of the above- mentioned mutations. It is, then, crucial to identify alternate routes of kinase pathway activation that sustain the constitutive or acquired resistant phenotype. p21-Activated Kinase (PAK) family proteins play an important role in the context of cancer progression, and are related to Ras pathway. Therefore, we focused on the involvement of PAK signaling pathway in the onset of cetuximab resistance.

Methods

We used different human colorectal cancer models, with or without KRAS/NRAS mutations. We also generated SW48 cells stably transfected with different K-RAS mutation. We tested the effects of PAK inhibition by PF-3758309 both in vitro and in vivo.

Results

All cell lines are sensitive to the PAK inhibitor PF-3758309, as shown by the inhibition of cell proliferation and cell viability, in both RAS wild type and RAS mutated cell lines. Upon PF-3758309 treatment we found an inhibition of the phosphorylation of different signal transducers downstream to PAKs, such as MEK1 (Ser298) and beta-Catenin (Ser675). Moreover, we found that PF-3758309 enhances EGFR phosphorylation in RAS mutated cells, an effect probably mediated by a beta-Catenin-dependent regulation of the DEP1 phosphatase. Based on these data, a combination of PF-3758309 with cetuximab is now under evaluation, in vitro and in vivo.

Conclusions

We demonstrated that PAK inhibition is effective in CRC cell lines, independently from the RAS mutational profile. Moreover, we hypothesize a PAK-dependent regulation of EGFR phosphorylation, mediated by beta-Catenin and DEP1. Based on our preliminary data, we plan to further investigate the role of PAK signaling in the onset of cetuximab resistance both in vitro and in vivo. by a beta-Catenin-dependent regulation of the DEP1 phosphatase. Based on these data, a combination of PF-3758309 with cetuximab is now under evaluation, in vitro and in vivo.

Legal entity responsible for the study

Prof. Roberto Bianco

Funding

Has not received any funding

Disclosure

All authors have declared no conflicts of interest.

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