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Tumor Discovery FBXW7 in Leukemia

In addition, FBXW7 also regulates the degradation (iii) MCL-1 inhibition: The stabilization of MCL-1 in
of other key proteins, such as the cell cycle regulator and FBXW7-deficient leukemia contributes to apoptosis
negative modulator p27. Stabilization of p27 leads to cell resistance and chemotherapy failure. Small molecule
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cycle arrest and may promote tumor cell proliferation. inhibitors of MCL-1, such as S63845, have shown
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Similarly, c-Jun, a transcription factor involved in potent activity in preclinical models of leukemia.
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cellular stress responses and proliferation regulation, is These inhibitors work by disrupting the interaction
also controlled by FBXW7. When FBXW7 undergoes between MCL-1 and pro-apoptotic proteins,
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mutation or loss of function, the stability of these substrates restoring apoptotic sensitivity and overcoming drug
increases, further driving tumor cell proliferation, survival, resistance.
and resistance to treatment. Notably, the accumulation of
oncogenic proteins such as c-Myc, Notch, cyclin E, and 4.2. Restoring FBXW7 function
MCL-1, due to impaired FBXW7 activity, becomes a central Restoring the function of FBXW7 represents a
factor in the pathogenesis of leukemia. This stabilization of promising therapeutic strategy, particularly for leukemia
key oncogenic proteins not only drives the progression of cases driven by FBXW7 mutations. These mutations
leukemia but also contributes to resistance to conventional frequently occur in the WD40 substrate recognition
therapies, highlighting FBXW7 as a critical target for domain, a critical region responsible for the specific
therapeutic intervention. binding between FBXW7 and its target proteins. Such
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4. Therapeutic targeting of FBXW7 in mutations impair FBXW7’s ability to bind its substrates,
thereby hindering the ubiquitination and subsequent
leukemia degradation of multiple oncogenic proteins, leading to
The role of FBXW7 in regulating oncogenic proteins makes their abnormal accumulation within cells. As a key tumor
it an attractive therapeutic target for treating leukemia, suppressor, FBXW7 is responsible for the degradation
particularly in cases where its loss contributes to resistance of several pivotal oncogenic proteins, including c-Myc,
to therapy. Therapeutic strategies are being developed to Notch, and cyclin E. Loss of FBXW7 function disrupts
either restore FBXW7 function or target the oncogenic cellular homeostasis, induces uncontrolled cell cycle
proteins stabilized by FBXW7 mutations (Figure 5). progression, impairs differentiation, and promotes
tumor development. In leukemia, the loss or mutation
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4.1. Targeting FBXW7 substrates of FBXW7 results in the sustained stabilization of these
Given that the loss of FBXW7 leads to the accumulation oncogenic substrates, which continuously drive leukemic
of specific oncogenic proteins, therapeutic strategies cell proliferation, accelerate disease progression,
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aimed at these substrates represent promising approaches and contribute to treatment resistance. Therefore,
for overcoming FBXW7-related oncogenesis. Current restoring or substituting FBXW7 function may reinstate
strategies include: proper degradation of these oncogenic proteins,
(i) c-Myc inhibition: The accumulation of c-Myc in suppress leukemic cell growth, and enhance treatment
FBXW7-deficient leukemias suggests that inhibiting responsiveness, offering a novel and hopeful direction
c-Myc could be a promising therapeutic approach. for targeted leukemia therapy. Several strategies are
BET-bromodomain inhibitors, such as JQ1, reduce being explored, including:
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c-Myc transcription by preventing BET proteins from (i) Gene therapy: Advances in CRISPR-Cas9 gene-editing
binding to acetylated histones at c-Myc target gene technology have made it possible to correct loss-of-
promoters. Preclinical studies have shown that BET function mutations in FBXW7, potentially restoring
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inhibitors can reduce c-Myc-driven transcription, its tumor-suppressive function. By introducing
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leading to decrease leukemia cell proliferation and functional copies of the FBXW7 gene into leukemia
enhanced apoptosis. 88 cells, it may be possible to re-establish the degradation
(ii) Notch inhibition: In T-ALL, aberrant Notch signaling of oncogenic proteins, thereby suppressing tumor
is a key driver of disease progression. Gamma- growth.
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secretase inhibitors (GSIs), which block the cleavage (ii) Small molecule stabilizers: Another approach involves
of Notch receptors and prevent the release of the development of small molecules that stabilize
NICD, have shown promise in preclinical models of FBXW7 or enhance its activity. By promoting the
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T-ALL. However, the use of GSIs has been limited interaction between FBXW7 and its substrates,
by gastrointestinal toxicity, highlighting the need these molecules could restore the tumor-suppressive
for more selective Notch inhibitors or combination function of FBXW7, even in cells with partial loss-of-
therapies that reduce off-target effects. 91 function mutations.

Volume 4 Issue 3 (2025) 6 doi: 10.36922/TD025150027