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Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
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KRAS and EGFR Mutations Differentially Alter ABC Drug Transporter Expression in Cisplatin-Resistant Non-Small Cell

Luca Jaromi1,2, Veronika Csongei1,2, Monika Vesel1,2

  • 1Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, University of Pecs, 2 Rokus Str, H-7624 Pecs, Hungary.

International Journal of Molecular Sciences
|June 2, 2021
PubMed

Insights

Lung adenocarcinoma (AC) subtypes with KRAS or EGFR mutations show distinct drug transporter (ABCB1, ABCG2) expression and WNT pathway alterations. These findings impact multidrug resistance (MDR) understanding and targeted therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Lung carcinoma, particularly non-small cell lung cancer (NSCLC) adenocarcinoma (AC), remains a global health challenge.
  • Driver mutations like KRAS and EGFR influence AC subtypes and treatment strategies.
  • Multidrug resistance (MDR) mediated by ABC drug transporters is a key factor in treatment failure.

Purpose of the Study:

  • To investigate the correlation between driver mutations (KRAS, EGFR) and the expression/function of ABC drug transporters (ABCB1, ABCG2) in lung adenocarcinoma.
  • To explore the impact of these mutations on the WNT signaling pathway and its role in cisplatin resistance (CR).

Main Methods:

  • Generated cisplatin-resistant (CR) cell lines (A549-KRAS, PC9-EGFR).
  • Analyzed gene expression of ABCB1 and ABCG2 transporters in cell lines and primary AC samples.
  • Investigated WNT pathway alterations (LEF1, RHOU, DACT1) in 3D multicellular aggregate cultures.

Main Results:

  • ABCB1 and ABCG2 gene expression levels differed in primary AC samples and correlated with specific driver mutations.
  • Increased ABCB1 and ABCG2 mRNA levels were observed in cisplatin-resistant A549 (KRAS) cells, with a different trend in PC9 (EGFR) cells.
  • Mutation-dependent alterations in WNT signaling pathway genes (LEF1, RHOU, DACT1) were identified.

Conclusions:

  • KRAS and EGFR driver mutations differentially influence ABC drug transporter expression in lung AC.
  • These mutations also differentially affect the cisplatin-induced WNT signaling microenvironment, impacting MDR.
  • Findings provide insights into mutation-specific therapeutic strategies for lung adenocarcinoma.
Keywords:
ABC drug transportersACEGFRKRASNSCLCWNT signalling

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