Integrative bioinformatics and drug response profiling identify MEK/ERK inhibition as a strategy to overcome venetoclax resistance in AML
- 1Department of Biochemistry, Faculty of Science, King Abdulaziz University
- 2Institute of Genomic Medicine Sciences, King Abdulaziz University
- 3Molecular Pathology Section, Pathology and Clinical Laboratory Medicine Administration, King Fahad Medical City
Abstract
Background: Drug resistance remains a key barrier to durable remission in acute myeloid leukemia (AML). A central but poorly resolved question is whether AML cells resistant to mechanistically distinct drugs converge on shared downstream survival dependencies, and whether those dependencies can be exploited therapeutically.
Methods: We compared transcriptional reprogramming across 3 independent resistance models derived from the FLT3-ITD-positive MV4-11 cell line: midostaurin-resistant cells, sorafenib-resistant cells, and a novel venetoclax-resistant line generated in our laboratory. Differential expression analysis, protein -protein interaction network analysis, hub-gene prioritization across multiple network centrality algorithms, and pathway enrichment analyses were performed on shared upregulated genes. Functional validation was performed using the MEK inhibitor selumetinib, and drug combination effects with the mTOR inhibitor PP242 were quantified using the Chou-Talalay combination index method.
Results: Despite the distinct mechanisms through which each drug exerts its effect, differential expression analysis identified 328 upregulated genes shared across at least 2 resistance conditions, with a meaningful subset common to all 3. Protein -protein interaction network analysis of these shared genes revealed a statistically non-random and functionally cohesive network, from which 10 hub genes: TLR4, PECAM1, CYBB, CXCL8, CASP8, ICAM1, CD33, CCL5, CD36, and JUN, emerged consistently across multiple independent network centrality algorithms. Pathway enrichment analyses converged prominently on the MAPK/ERK cascade, with multiple independent terms pointing specifically to positive regulation of ERK1/2 signaling. Functional validation using the MEK inhibitor selumetinib revealed that venetoclax-resistant cells were modestly more sensitive to MAPK inhibition than parental cells, with growth suppression driven predominantly by G0/G1 cell-cycle arrest rather than apoptosis, indicating a cytostatic rather than cytotoxic mechanism. Combined MEK and mTOR inhibition produced synergistic antiproliferative effects, with greater synergy observed in resistant cells.
Conclusion: Collectively, these findings suggest that MV4-11 cells, despite diverging in their proximal resistance mechanisms, converge on a conserved ERK-mediated survival program, positioning the MAPK pathway as a broadly relevant therapeutic vulnerability and supporting MEK-based combination strategies to overcome acquired resistance in AML.
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BibTeX
@article{alogailan2026integrative,
title = {{Integrative bioinformatics and drug response profiling identify MEK/ERK inhibition as a strategy to overcome venetoclax resistance in AML}},
author = {Abeer A. Al-Ogailan and Sherin Bakhashab and Abdul Ali Peer-Zada and Farid Ahmed},
journal = {Frontiers in Oncology},
year = {2026},
month = nov,
doi = {10.3389/fonc.2026.1944265},
url = {https://www.frontiersin.org/articles/10.3389/fonc.2026.1944265/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Integrative bioinformatics and drug response profiling identify MEK/ERK inhibition as a strategy to overcome venetoclax resistance in AML
AU - Abeer A. Al-Ogailan
AU - Sherin Bakhashab
AU - Abdul Ali Peer-Zada
AU - Farid Ahmed
PY - 2026
DA - 2026/11/09
JO - Frontiers in Oncology
DO - 10.3389/fonc.2026.1944265
UR - https://www.frontiersin.org/articles/10.3389/fonc.2026.1944265/full
AB - Background: Drug resistance remains a key barrier to durable remission in acute myeloid leukemia (AML). A central but poorly resolved question is whether AML cells resistant to mechanistically distinct drugs converge on shared downstream survival dependencies, and whether those dependencies can be exploited therapeutically. Methods: We compared transcriptional reprogramming across 3 independent resistance models derived from the FLT3-ITD-positive MV4-11 cell line: midostaurin-resistant cells, sorafenib-resistant cells, and a novel venetoclax-resistant line generated in our laboratory. Differential expression analysis, protein -protein interaction network analysis, hub-gene prioritization across multiple network centrality algorithms, and pathway enrichment analyses were performed on shared upregulated genes. Functional validation was performed using the MEK inhibitor selumetinib, and drug combination effects with the mTOR inhibitor PP242 were quantified using the Chou-Talalay combination index method. Results: Despite the distinct mechanisms through which each drug exerts its effect, differential expression analysis identified 328 upregulated genes shared across at least 2 resistance conditions, with a meaningful subset common to all 3. Protein -protein interaction network analysis of these shared genes revealed a statistically non-random and functionally cohesive network, from which 10 hub genes: TLR4, PECAM1, CYBB, CXCL8, CASP8, ICAM1, CD33, CCL5, CD36, and JUN, emerged consistently across multiple independent network centrality algorithms. Pathway enrichment analyses converged prominently on the MAPK/ERK cascade, with multiple independent terms pointing specifically to positive regulation of ERK1/2 signaling. Functional validation using the MEK inhibitor selumetinib revealed that venetoclax-resistant cells were modestly more sensitive to MAPK inhibition than parental cells, with growth suppression driven predominantly by G0/G1 cell-cycle arrest rather than apoptosis, indicating a cytostatic rather than cytotoxic mechanism. Combined MEK and mTOR inhibition produced synergistic antiproliferative effects, with greater synergy observed in resistant cells. Conclusion: Collectively, these findings suggest that MV4-11 cells, despite diverging in their proximal resistance mechanisms, converge on a conserved ERK-mediated survival program, positioning the MAPK pathway as a broadly relevant therapeutic vulnerability and supporting MEK-based combination strategies to overcome acquired resistance in AML.
SN - 2234-943X
ER -