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van Waardenburg et al. Cancer Drug Resist 2021;4:837-41  Page 3

               specifically focus on the current combination treatment of venetoclax with the hypomethylating agents
               (HMA) decitabine or azacytidine that improves outcomes in older patients over the standard of care
               therapies. HMAs are pyrimidine analogs that are incorporated into the DNA and inhibit the action of DNA
               methyltransferases (DNMT). They discuss the change in treatment with high cytotoxic doses to long
               exposures with a lower dose that affects epigenetic modifications via DNA hypomethylation that stimulates
               differentiation and tumor suppression without cell cycle arrest. They reviewed the differences in the
               mechanism of action of the different hypomethylating pyrimidine analogs and the cellular response they
               evoke, including those that cause drug resistance. In addition, they review the mechanism of action of
               venetoclax, an oral inhibitor of the anti-apoptotic protein BCL2, which, together with BCLX  and MCL1,
               are frequently overexpressed in AML. Several potential mechanisms of acquired venetoclax resistance in
               AML and other leukemias are discussed, including modulation of expression levels of the BCL2 target and
               compensatory upregulation of BCL2 paralogs and acquired mutations in BCL2 that affect drug binding.
               Moreover, the mechanism of action and the development of resistance to this combination therapy are
               discussed from a molecular viewpoint. They conclude that this combination therapy is successful, but it is
               critical to evaluate modification in dosing schedules to avoid acquired resistance.

               Recent successes with PARP inhibitors have led to investigations of other DNA repair targets as potential
               treatments. One such target is CHK1, which is an important regulator of the DNA repair checkpoint
               activated upon replication stress. Inhibition of CHK1 results in increased replication stress, accumulation of
               unrepaired DNA double-strand breaks, and cell death through apoptosis and mitotic catastrophe. Several
               CHK1 inhibitors have shown preclinical and clinical activity, and as with most targeted therapies, acquired
               resistance is an issue, including compensatory PI3K and MAPK pathway activation and induction of anti-
               apoptotic proteins. In their report, Lee et al.  hypothesized that the upstream EGFR pathway could also
               serve as a resistance mechanism and that inhibition of EGFR would enhance the anti-tumor activity of the
               CHK1 inhibitor prexasertib in triple-negative breast cancer. Indeed, EGFR activation with EGF reduced
               cellular sensitivity to CHK1 inhibition, and conversely, inhibition of EGFR with erlotinib enhanced cellular
               cytotoxicity with prexasertib in several in vitro and in vivo models of triple negative breast cancer. These
               data are consistent with similar EGFR/CHK1 combinations in other tumor types, including head and neck
               cancers . A recently reported clinical trial demonstrated that prexasertib could be safely combined with
               cetuximab and radiation . However, biomarkers to select the patients most likely to benefit from these
               combinations are still needed.

               It is well-established that genomic instability is a hallmark of carcinogenesis, and a mutation in TP53 is an
               initiating event that triggers downstream activation of oncogenic pathways leading to cancer. Interestingly,
               Dr. Juhlin  discusses aberrant DNA repair as a process that may facilitate clonal evolution of well-
               differentiated thyroid carcinoma into anaplastic thyroid cancer. With recent advances in next-generation
               sequencing technology, there is an increased ability to interrogate the genomic landscape of thyroid cancers
               and track phylogenetic clusters as tumors progressively de-differentiated into anaplastic thyroid cancer.
               Importantly, mismatch repair deficiency was noted, and the potential benefit of immune checkpoint
               inhibitors in this setting must be recognized for this aggressive disease.

               Another mechanism by which DNA repair influences cancer treatment is by affecting tumor response to
               radiation. Fabbrizi and Parsons  report on current and future perspectives of DNA damage response to
               enhance radiation for head and neck cancer. Authors discuss the differential radiation sensitivities of HPV-
               associated vs. non-HPV-associated head and neck cancer, likely due to ineffective DNA damage
               checkpoints and DNA repair mechanisms in HPV-associated head and neck cancers. They also discuss the
               role of tumor hypoxia in radiation resistance. Based on these pathways, radiation sensitization strategies are
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