Biology subjects

Frederick, M. I.

Publications and source records attributed to Frederick, M. I..

3 recordsLinked to original sources

bioRxiv2026

Pharmacological inhibition of LIN28A promotes imatinib sensitivity in CML resistance

Resistance to tyrosine kinase inhibitors (TKIs) remains a critical challenge in chronic myeloid leukemia (CML), particularly when driven by mechanisms independent of BCR-ABL1 kinase-domain mutations. Building on the identification of the RNA-binding protein LIN28A as a driver of imatinib resistance, we evaluated emerging LIN28 inhibitors as potential sensitizing agents. Screening three small molecules in an imatinib-resistant (ImR) K562 model identified LIN28i-1632 as uniquely synergistic with imatinib (synergy score: 12.07), reducing cell proliferation by 71.15%. Quantitative DIA and TMT proteomics revealed that this synergy is characterized by significant proteomic remodelling, including the downregulation of the canonical LIN28 target HMGA1 and the activation of apoptotic and G2/M cell cycle checkpoint programs. Mechanistically, phosphoproteome and kinome profiling showed suppressed AKT/RPS6K and CDK signalling. We further demonstrate that LIN28i-1632 promotes sensitivity by reducing BCR-ABL protein abundance and attenuating the AKT survival axis through RICTOR downregulation and PTEN restoration. Collectively, our findings establish pharmacological LIN28 inhibition as a viable strategy to overcome TKI resistance by simultaneously engaging cell-cycle arrest and dismantling the AKT-mediated survival network.

cancer biology↗

bioRxiv2025

LIN28A-Dependent Kinome and Phosphoproteome Reprogramming Promotes Imatinib Resistance

Chronic myeloid leukemia (CML) resistance to BCR-ABL tyrosine kinase inhibitors (TKIs) can arise from ABL kinase domain mutations, BCR-ABL fusion gene amplification, or kinase-independent mechanisms. To investigate imatinib-resistance, we performed quantitative mass spectrometry comparing the proteome and phosphoproteome of K562 cells (a standard CML model) and ImR cells, an imatinib-resistant K562 derivative that also exhibits cross-resistance to second- and third-generation BCR-ABL TKIs. In addition to revealing global proteome and phosphoproteome changes associated with drug resistance, we identified LIN28A--a multi-functional RNA-binding protein--as a critical mediator of imatinib resistance. LIN28A was significantly overexpressed and hyperphosphorylated in ImR cells. Depleting LIN28A via shRNA restored imatinib sensitivity, while its ectopic expression in parental K562 cells induced imatinib resistance. Mechanistically, LIN28A coordinates an extensive kinase-substrate network regulating proliferation, survival, and metabolism to drive resistance. Notably, pharmacological inhibition of LIN28A-dependent kinases (PKC, AKT, SGK1, and RPS6K) suppressed ImR proliferation. Midostaurin, a clinical PKC/FLT3 inhibitor used in FLT3-ITD--positive AML, potently re-sensitized ImR cells to imatinib. Our findings suggest that targeting LIN28A and its downstream effectors, particularly PKC, could overcome resistance to imatinib and next-generation BCR-ABL inhibitors.

cancer biology↗

bioRxiv2024

Targeting FEN1 to enhance efficacy of PARP inhibition in triple-negative breast cancer

Patients with triple-negative breast cancer (TNBC) have limited targeted therapeutic options. PARP inhibitors (PARPi) have demonstrated an important role for BRCA-mutant patients with early TNBC. Combination approaches with PARPi can broaden the use of PARPi to a larger cohort of TNBC patients. We selected six genes from our previously identified 63-gene signature that was associated with PARPi response. siFEN1 increased cells in G2/M arrest, DNA damage and particularly apoptosis. Targeting FEN1 with a chemical inhibitor enhanced the efficacy of PARPi in 7/10 cell lines, and synergy was demonstrated mainly in PARPi-resistant TNBC cell lines. A BRCA2-mutant cell line with acquired resistance to olaparib (HCC1395-OlaR) was strongly synergistic, with a combination index value of 0.20. The combination of PARPi and FEN1 inhibition also showed synergy in a PARPi-resistant xenograft-derived organoid model. Two mechanisms which explain the underlying efficacy are rapid progression in DNA replication fork speed and enhancement of DNA damage. The combination induced the highest fork speed (47% difference in comparison to control, P<0.0001) when FEN1 inhibition and PARPi equally increased fork speed individually in a cell line with a pre-existing increase in replication stress. The combination also increased DNA damage at lower drug concentrations, driving response in most of the synergistic cell lines. Gene expression analysis suggested that the sensitizing role of FEN1 inhibition in PARPi-resistant cell lines may be due to downregulation of pathways including mismatch repair. Therefore, targeting FEN1 shows great therapeutic potential as a targeted combination approach, particularly in the context of PARPi-resistant TNBC.

cancer biology↗