Cell-specific models reveal conformation-specific RAF inhibitor combinations that synergistically inhibit ERK signaling in pancreatic cancer cells

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15110%2F24%3A73627512" target="_blank" >RIV/61989592:15110/24:73627512 - isvavai.cz</a>

Result on the web

<a href="https://www.cell.com/cell-reports/fulltext/S2211-1247(24)01061-1" target="_blank" >https://www.cell.com/cell-reports/fulltext/S2211-1247(24)01061-1</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.celrep.2024.114710" target="_blank" >10.1016/j.celrep.2024.114710</a>

Result language

angličtina

Original language name

Cell-specific models reveal conformation-specific RAF inhibitor combinations that synergistically inhibit ERK signaling in pancreatic cancer cells

Original language description

Pancreatic ductal adenocarcinoma (PDAC) presents significant challenges for targeted clinical interventions due to prevalent KRAS mutations, rendering PDAC resistant to RAF and MEK inhibitors (RAFi and MEKi). In addition, responses to targeted therapies vary between patients. Here, we explored the differential sensitivities of PDAC cell lines to RAFi and MEKi and developed an isogenic pair comprising the most sensitive and resistant PDAC cells. To simulate patient- or tumor specific variations, we constructed cell-line-specific mechanistic models based on protein expression profiling and differential properties of KRAS mutants. These models predicted synergy between two RAFi with different conformation specificity (type I½ and type II RAFi) in inhibiting phospho-ERK (ppERK) and reducing PDAC cell viability. This synergy was experimentally validated across all four studied PDAC cell lines. Our findings underscore the need for combination approaches to inhibit the ERK pathway in PDAC.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

10601 - Cell biology

Project

—

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2024

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Cell Reports

ISSN

2211-1247

e-ISSN

—

Volume of the periodical

43

Issue of the periodical within the volume

9

Country of publishing house

US - UNITED STATES

Number of pages

27

Pages from-to

114710

UT code for WoS article

001309740500001

EID of the result in the Scopus database

2-s2.0-85205275228