Small-molecule inhibitors of DNA damage-repair pathways: an approach to overcome tumor resistance to alkylating anticancer drugs

Small cell lung cancer (SCLC), accounting for about 15% of all cases of lung cancer worldwide, is the most lethal form of lung cancer. Despite an initially high response rate of SCLC to standard treatment, almost all patients are invariably relapsed within one year. Effective therapeutic strategies are urgently needed to improve clinical outcomes. Replication stress is a hallmark of SCLC due to several intrinsic factors. As a consequence, constitutive activation of the replication stress response (RSR) pathway and DNA damage repair system is involved in counteracting this genotoxic stress. Therefore, therapeutic targeting of such RSR and DNA damage repair pathways will be likely to kill SCLC cells preferentially and may be exploited in improving chemotherapeutic efficiency through interfering with DNA replication to exert their functions. Here, we summarize potentially valuable targets involved in the RSR and DNA damage repair pathways, rationales for targeting them in SCLC treatment and ongoing clinical trials, as well as possible predictive biomarkers for patient selection in the management of SCLC.

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Abstract 1137: PRMT5 inhibition regulates alternative splicing and DNA damage repair pathways in SF3B1 R625G expressing uveal melanoma cells

10.1158/1538-7445.am2021-1137 ◽

2021 ◽

Author(s):

Koichi Ito ◽

Venkat Thodima ◽

Jack Carter ◽

Neha Bhagwat ◽

Monisha Sivakumar ◽

...

Keyword(s):

Dna Damage ◽

Alternative Splicing ◽

Uveal Melanoma ◽

Dna Damage Repair ◽

Melanoma Cells ◽

Damage Repair ◽

Repair Pathways

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A Comprehensive Analysis of Alterations in DNA Damage Repair Pathways Reveals a Potential Way to Enhance the Radio-Sensitivity of Esophageal Squamous Cell Cancer

Frontiers in Oncology ◽

10.3389/fonc.2020.575711 ◽

2020 ◽

Vol 10 ◽

Author(s):

Guangchao Wang ◽

Shichao Guo ◽

Weimin Zhang ◽

Zhangfu Li ◽

Jiancheng Xu ◽

...

Keyword(s):

Dna Damage ◽

Squamous Cell ◽

Squamous Cell Cancer ◽

Cell Cancer ◽

Dna Damage Repair ◽

Comprehensive Analysis ◽

Esophageal Squamous Cell Cancer ◽

Damage Repair ◽

Repair Pathways ◽

Radio Sensitivity

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Antitumor Activity of a Novel Tyrosine Kinase Inhibitor AIU2001 Due to Abrogation of the DNA Damage Repair in Non-Small Cell Lung Cancer Cells

International Journal of Molecular Sciences ◽

10.3390/ijms20194728 ◽

2019 ◽

Vol 20 (19) ◽

pp. 4728 ◽

Cited By ~ 2

Author(s):

Hwani Ryu ◽

Hyun-Kyung Choi ◽

Hyo Jeong Kim ◽

Ah-Young Kim ◽

Jie-Young Song ◽

...

Keyword(s):

Lung Cancer ◽

Dna Damage ◽

Tyrosine Kinase ◽

Small Molecule ◽

Parp Inhibitor ◽

Dna Damage Repair ◽

Class Iii ◽

Damage Repair ◽

Repair Genes

Class III receptor tyrosine kinase (RTK) inhibitors targeting mainly FLT3 or c-KIT have not been well studied in lung cancer. To identify a small molecule potentially targeting class III RTK, we synthesized novel small molecule compounds and identified 5-(4-bromophenyl)-N-(naphthalen-1-yl) oxazol-2-amine (AIU2001) as a novel class III RKT inhibitor. In an in vitro kinase profiling assay, AIU2001 inhibited the activities of FLT3, mutated FLT3, FLT4, and c-KIT of class III RTK, and the proliferation of NSCLC cells in vitro and in vivo. AIU2001 induced DNA damage, reactive oxygen species (ROS) generation, and cell cycle arrest in the G2/M phase. Furthermore, AIU2001 suppressed the DNA damage repair genes, resulting in the ‘BRCAness’/‘DNA-PKness’ phenotype. The mRNA expression level of STAT5 was downregulated by AIU2001 treatment and knockdown of STAT5 inhibited the DNA repair genes. Our results show that compared to either drug alone, the combination of AIU2001 with a poly (ADP-ribose) polymerase (PARP) inhibitor olaparib or irradiation showed synergistic efficacy in H1299 and A549 cells. Hence, our findings demonstrate that AIU2001 is a candidate therapeutic agent for NSCLC and combination therapies with AIU2001 and a PARP inhibitor or radiotherapy may be used to increase the therapeutic efficacy of AIU2001 due to inhibition of DNA damage repair.

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A Novel Role for Cathepsin S as a Potential Biomarker in Triple Negative Breast Cancer

Journal of Oncology ◽

10.1155/2019/3980273 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 3

Author(s):

Richard D. A. Wilkinson ◽

Roberta E. Burden ◽

Sara H. McDowell ◽

Darragh G. McArt ◽

Stephen McQuaid ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Dna Damage ◽

Adjuvant Therapy ◽

Dna Damage Repair ◽

Cathepsin S ◽

Damage Repair ◽

Potential Biomarker ◽

Repair Pathways ◽

Improved Outcome

Cathepsin S (CTSS) has previously been implicated in a number of cancer types, where it is associated with poor clinical features and outcome. To date, patient outcome in breast cancer has not been examined with respect to this protease. Here, we carried out immunohistochemical (IHC) staining of CTSS using a breast cancer tissue microarray in patients who received adjuvant therapy. We scored CTSS expression in the epithelial and stromal compartments and evaluated the association of CTSS expression with matched clinical outcome data. We observed differences in outcome based on CTSS expression, with stromal-derived CTSS expression correlating with a poor outcome and epithelial CTSS expression associated with an improved outcome. Further subtype characterisation revealed high epithelial CTSS expression in TNBC patients with improved outcome, which remained consistent across two independent TMA cohorts. Furtherin silicogene expression analysis, using both in-house and publicly available datasets, confirmed these observations and suggested high CTSS expression may also be beneficial to outcome in ER-/HER2+ cancer. Furthermore, high CTSS expression was associated with the BL1 Lehmann subgroup, which is characterised by defects in DNA damage repair pathways and correlates with improved outcome. Finally, analysis of matching IHC analysis reveals an increased M1 (tumour destructive) polarisation in macrophage in patients exhibiting high epithelial CTSS expression. In conclusion, our observations suggest epithelial CTSS expression may be prognostic of improved outcome in TNBC. Improved outcome observed with HER2+ at the gene expression level furthermore suggests CTSS may be prognostic of improved outcome in ER- cancers as a whole. Lastly, from the context of these patients receiving adjuvant therapy and as a result of its association with BL1 subgroup CTSS may be elevated in patients with defects in DNA damage repair pathways, indicating it may be predictive of tumour sensitivity to DNA damaging agents.

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