EXPLORING DRUG POTENTIAL OF MYELOID/LYMPHOID LINEAGE GENE MUTATIONS IN ADVANCED-PHASE CML USING DRUG DISCOVERY TOOLS: INSIGHTS FOR PRECISION ONCOLOGY IN BLAST CRISIS CML IN THE POST-COVID-19 ERA
Main Article Content
Keywords
Blast crisis CML, Drug repurposing, Precision oncology, AML/ALL-lineage mutations, Whole- exome sequencing, PanDrugs (or AI-driven drug discovery), Tyrosine kinase inhibitor resistance.
Abstract
Background: The COVID-19 pandemic demonstrated the power of drug repurposing as a rapid, cost-effective strategy to address urgent medical needs, leveraging existing drugs like dexamethasone and remdesivir through accelerated testing and approval pathways. This approach is particularly crucial for blast crisis chronic myeloid leukemia (BC-CML), one of the most aggressive and treatment-resistant forms of cancer in the 21st century, where TKI resistance and complex AML/ALL-like genomic alterations lead to poor survival rates (often <12 months). Blast crisis chronic myeloid leukemia (BC-CML) is a lethal phase of CML marked by relapses, treatment resistance and poor survival. While tyrosine kinase inhibitors (TKIs) are effective in chronic-phase CML, BC-CML often acquires additional mutations resembling acute leukemias (AML/ALL), necessitating novel therapeutic strategies. This study investigated AML- and ALL-associated gene mutations in BC-CML using whole-exome sequencing (WES) and AI-based drug repositioning via PanDrugs to identify precision therapy options.
Methods: The study enrolled CML patients across disease phases: chronic phase (20%), accelerated phase (33.3%), and blast crisis (46.7%), alongside healthy controls. Genomic DNA from blood/bone marrow underwent WES, with variants analyzed using GRCh38 alignment and filtered against population databases. Mutations were annotated using ClinVar, dbSNP, and COSMIC, prioritizing those linked to AML/ALL pathways. Druggability was assessed using PanDrugs, which cross-references mutations with FDA-approved and investigational drugs. Clinical outcomes were correlated with mutational profiles.
Results: BC-CML patients showed a 22.2-fold higher mutational burden versus chronic-phase CML (2531 vs. 114 variants). Key findings included:
AML-Lineage Mutations (and corresponding Drugs):
- Epigenetic Regulators: DNMT3A (hypomethylating agents: azacitidine), TET2 (vitamin C + TKIs), IDH1 (ivosidenib), EZH2 (tazemetostat).
- Signaling Pathways: NF1 (MEK inhibitors: trametinib), RPTOR (mTOR inhibitors: everolimus), JAK2 (ruxolitinib), CBL (dasatinib).
- Oncogenic Drivers: PML (arsenic trioxide), BCL2 (venetoclax), AKT1 (capivasertib).
ALL-Lineage Mutations (and corresponding Drugs):
- BCR-ABL1-Independent Targets: BCL2 (venetoclax), BCL6 (homoharringtonine), KMT2A (menin inhibitors: revumenib).
- Kinase Alterations: EGFR (zanubrutinib, osimertinib), FBXW7 (BET inhibitors: molibresib).
EGFR mutations showed the highest increase in BC-CML and correlated with extreme leukocytosis. BCL2 mutations (43% of BC-CML cases) were universally fatal within 12 months, highlighting venetoclax’s potential. STAB1 and ACIN1 were novel non-druggable candidates requiring further study.
Conclusions: BC-CML harbors clinically actionable AML/ALL-like mutations, identifiable via WES and AI tools. Drug repositioning (e.g., venetoclax for BCL2, ivosidenib for IDH1) offers a pragmatic approach to overcome TKI resistance.
Clinical Recommendations:
- Routine Genomic Screening: Implement WES/NGS at BC-CML diagnosis to detect AML/ALL-lineage mutations (e.g., BCL2, IDH1, NF1).
- Targeted Therapies:
- BCL2: Integrate venetoclax + TKIs.
- IDH1/EGFR: Use ivosidenib or zanubrutinib in combination regimens.
- NF1/RPTOR: Trial trametinib or everolimus with dose-adjusted TKIs.
- Trial Priorities: Phase II studies for menin inhibitors (KMT2A), BET inhibitors (FBXW7), and MEK inhibitors (NF1).
- Global Frameworks: Establish mutation registries and cost-effective testing hubs to expand access to precision therapies.
This study validates a precision oncology pipeline for BC-CML, leveraging existing AML/ALL drugs to address an urgent unmet need.
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