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Tumor Discovery FBXW7 in Leukemia

a one-size-fits-all treatment approach ineffective, 5.2. Future directions
necessitating the development of personalized To overcome these challenges, several key areas of research
therapeutic strategies based on the specific mutation should be prioritized:
type and substrate stabilization pattern. This approach (i) Advanced preclinical models: Developing genetically
requires therapeutic strategies targeting the specific engineered mouse models and patient-derived
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degradation dysregulation of substrates to improve the xenografts that accurately recapitulate the spectrum
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precision and efficacy of treatment. of FBXW7 mutations found in human leukemia will be
(ii) Redundancy in degradation pathways: Other E3 essential for studying the biological consequences of
ligases, such as β-TrCP, may compensate for the loss FBXW7 loss and testing novel therapeutic strategies.
of FBXW7 in certain contexts, reducing the efficacy These models will also help to delineate the contexts
of therapies aimed at restoring FBXW7 function. in which FBXW7 plays a critical role in tumor
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Understanding the redundancy within the ubiquitin- suppression.
proteasome system and identifying the contexts (ii) Identification of novel substrates: Although several
in which FBXW7 is indispensable will be key to key substrates of FBXW7 have been identified, it is
developing more effective targeted therapies. likely that additional oncogenic proteins are regulated
(iii) Therapeutic resistance: Leukemia cells with FBXW7 by FBXW7. High-throughput proteomic approaches,
mutations often develop resistance to standard such as mass spectrometry-based interactome
chemotherapies and targeted therapies. This resistance studies, could be used to identify new substrates and
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is driven by the stabilization of oncogenic substrates expand the repertoire of therapeutic targets.
such as MCL-1 and c-Myc, which promote cell survival (iii) Combination therapies: Given the complexity of
even in the presence of cytotoxic agents. Overcoming FBXW7’s role in regulating multiple oncogenic
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this resistance will require the development of more pathways, combination therapies that target both
effective therapies that target these stabilized proteins FBXW7 substrates and compensatory mechanisms
or their downstream signaling pathways. are likely to be more effective than monotherapies.
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(iv) “Undruggable” substrates: Many key FBXW7 Rationally designed combination therapies that
substrates, such as c-Myc and MCL-1, have long been include c-Myc or MCL-1 inhibitors, in conjunction
considered “undruggable” due to the lack of well- with standard chemotherapy or immune checkpoint
defined small molecule binding pockets. However, inhibitors, could enhance treatment efficacy and
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recent advancements in drug discovery, particularly overcome resistance.
the development of PROTAC technology, have (iv) Restoring FBXW7 function: Gene therapy and
opened new possibilities for targeting these proteins. small molecule stabilizers offer promising avenues
PROTACs overcome the limitation of traditional for restoring FBXW7 function in leukemia cells.
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small molecule inhibitors, which cannot directly bind Continued research into the mechanisms that
to their targets, by inducing the degradation of target regulate FBXW7 stability and activity will be crucial
proteins. This approach provides a novel pathway for developing these therapies. In addition, small
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for treating these challenging targets. Nevertheless, molecules that enhance the interaction between
there remain several technical challenges that must FBXW7 and its substrates may provide an alternative
be addressed for clinical success. First, the target approach to restoring its tumor-suppressive function.
selectivity of PROTACs needs to be further improved (v) Biomarker development for personalized medicine:
to ensure specific degradation of the target protein As our understanding of the molecular consequences
without triggering off-target effects. Second, the of FBXW7 mutations deepens, incorporating FBXW7
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bioavailability and pharmacokinetic properties of status as a biomarker of therapeutic response into
PROTACs require optimization, particularly in clinical practice becomes essential for personalized
terms of stability in vivo and the ability to penetrate treatment. Biomarkers of therapeutic response
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cell membranes. In addition, the efficacy of are molecular or genetic features that predict how
PROTACs in different types of tumors or other a patient will respond to specific treatments. In
diseases is not yet fully understood, and enhancing cancers such as leukemia, these biomarkers reflect
their effectiveness in heterogeneous diseases remains tumor cell sensitivity or resistance to particular
a significant challenge. Only by overcoming these therapies. For instance, the status of FBXW7, whether
technical obstacles can PROTACs achieve true clinical through mutations or functional loss, serves as a key
translation and drive the advancement of targeted indicator of how tumor cells will respond to targeted
therapies for “undruggable” substrates. therapies or conventional chemotherapy. FBXW7
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Volume 4 Issue 3 (2025) 8 doi: 10.36922/TD025150027