Page 45 - ARNM-3-1

Advances in Radiotherapy
& Nuclear Medicine EZH2 inhibition in ARID1A-deficient TNBC

radiotherapy, tazemetostat, and immunotherapy immune response, overcoming tumor radioresistance,
(nivolumab and ipilimumab), achieving an overall survival and generating anti-tumor non-targeted effects can
of 37 months. Chen et al. described a case report of significantly enhance the success of radiation treatments. 99
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a patient with INI1 deficient-advanced squamous cell In addition to its pivotal role in cellular processes, such
lung cancer exhibiting progressive disease while on as differentiation, proliferation, and tumor suppression,
maintenance pembrolizumab. Unfortunately, the patient the SWI/SNF complex is crucial in the DNA damage
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did not respond to sequential delivery of tazemetostat. In response by propagating DNA damage signals and
this case, molecular sequencing analysis did not reveal enabling DNA repair proteins to access damage sites.
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a SMARCB1 deletion, suggesting that the loss of INI1 Components of the SWI/SNF complex are essential for the
protein was due to epigenetic regulation rather than non-homologous end joining (NHEJ) repair of DSBs in
mutation. Clinical trials evaluating tazemetostat in human cancer cells, suggesting that the SWI/SNF complex
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combination with immunotherapy are currently enrolling may contribute to resistance against therapeutic agents that
participants: Tazemetostat combined with pembrolizumab induce DNA damage, including radiation. ARID1A, a
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for urothelial carcinoma (NCT03854474), whereas another gene encoding the BAF250a protein, is a key component of
trial combines tazemetostat with durvalumab for advanced the SWI/SNF complex that facilitates NHEJ by promoting
solid tumors (NCT04705818). NCT04705818 includes the accumulation of Ku70/Ku80 proteins at DSBs, thereby
solid tumors with the presence of tertiary lymphoid conferring resistance to ionizing radiation. The loss of
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structures, which are found in approximately 60% of breast ARID1A impairs checkpoint activation and DNA DSB
cancer cases and are particularly common in TNBC. 95
repair, sensitizing cells to radiation. Andrade et al.
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5.2. Radiotherapy showed that genetic inhibition of ARID1A leads to an
accumulation of radiation-induced DSBs, sensitizing
Since EZH2 inhibition appears to decrease cancer cell TNBC cells to radiation. Bakr et al. showed that the
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migration and tumor metastasis more than it reduces loss of ARID1A promotes the accumulation of micronuclei
primary tumor growth in most solid tumors, exploring and activation of the cGAS-STING pathway, as well as
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combinations with radiation to achieve primary tumor increases the expression of immunomodulatory cytokines
control is warranted. Radiation also has immunomodulatory and chemokines from radiotherapy treatment. Notably,
effects, with different radiation schemes inducing various low ARID1A expression in cancer patients receiving
lymphoid and myeloid responses, as well as modulating radiotherapy was associated with higher infiltration of
checkpoint expression. 96
various immune cells. 101
Radiotherapy induces DNA damage through direct
The interaction mechanism between EZH2 and radiation
ionization or indirectly through interactions between is not well understood. Pre-clinical studies indicate
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free radicals formed by ionization of water surrounding that EZH2 inhibitors can enhance the radiosensitivity of
DNA, resulting in single- or double-strand breaks glioma cells, atypical teratoma or rhabdoid tumor cells,
(DSBs). Oxygen molecules react with these radicals, and pancreatic cancer cells. 39,102-104 In a cohort of patients
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altering the chemical composition of DNA strand breaks
and facilitating their recognition by DNA damage repair with nasopharyngeal cancer treated with radiation or
chemoradiation, increased H3K27me3 expression was
enzymes. Under hypoxic conditions, radicals chemically associated with chemoradioresistance. 39,105 Elevated EZH2
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react with free protons, reverting to their original levels correlate with radiation resistance; however, pre-
form, which impedes the fixation of DNA damage and clinical evidence suggests that high-dose radiotherapy
contributes to radioresistance. In addition, hypoxia alone may reduce EZH2 protein expression in vitro and at
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activates oxygen-sensitive signaling pathways, such as the mRNA level in vivo through p53-mediated inhibition of
those mediated by hypoxia-inducible factor transcription 106-108 109
factors, the unfolded protein response, and the mTOR transcription factor E2F1. Klaus et al. reported that
pathway. These pathways influence key biological radiation delivered concurrently with or after treatment
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processes, including mitosis, apoptosis, and angiogenesis, with the EZH2 inhibitor tazemetostat induced robust
impacting radiosensitivity. Hypoxia-induced global antiproliferative activity and reduced clonogenic potential
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changes in histone modifications and DNA methylation, in tested atypical rhabdoid tumor cell lines.
such as increased levels of H3K4me3 and decreased Gounder et al. reported on a patient with SMARCB1/
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levels of H3K27me3, lead to transcriptional changes that INI1-negative poorly differentiated chordoma treated with
also affect radiosensitivity. 97,98 Combining agents that tazemetostat and sequential radiotherapy. It was found
inhibit both DNA methylation and histone acetylation that EZH2 inhibition, evidenced by decreased H3K27me3
may enhance radiosensitivity. Inducing an anti-tumor marks, led to a notable increase in intratumoral and
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Volume 3 Issue 1 (2025) 37 doi: 10.36922/arnm.5132