**1. Introduction**

Lung cancer is one of the most commonly occurring cancers worldwide. Non-small cell lung cancer (NSCLC) accounts for more than 84% of all lung cancers [1]. Despite recent advances in our understanding of the molecular and genetic basis of lung cancer and improvements in therapy, the 5-year survival rate of patients with NSCLC in both Korea (23.7%) and the United States (23%) is lower than that for many other leading cancers [1,2]. The standard chemotherapy treatment used for NSCLC is either the platinum-based (cisplatin, carboplatin, etc.) or taxane-based (paclitaxel, docetaxel, etc.) regimens, or epidermal growth factor receptor (EGFR) inhibitors. However, because of the lack of response or resistance to those therapies, many patients with NSCLC consider new alternative therapies or receive combination therapies [3]. Therefore, the development of novel drugs or strategies of combination therapy with existing drugs is urgently required.

Ionizing radiation (IR) is directly cytotoxic through the induction of DNA single- or double-strand breaks (DSB) and indirectly cytotoxic through the generation of reactive oxygen species (ROS), leading to tumor cell death and thus cancer treatment. Similarly, platinum- or taxane-based chemotherapeutic agents inhibit cell mitosis through the induction of DNA damage. DNA lesions induced by IR or cytotoxic agents can be repaired by six major DNA repair pathways: base excision repair, nucleotide excision repair, direct repair (i.e., O<sup>6</sup> -alkylguanine DNA alkyltransferase directly repairs DNA damaged lesions by removing O<sup>6</sup> -methylguanine), mismatch repair, homologous recombination (HR), and non-homologous end-joining pathways. NSCLC is characterized by genomic instability with mutations and translocations in oncogenes, such as the *Ki-ras2 Kirsten rat sarcoma viral oncogene homolog proto-oncogene* (*KRAS*), *EGFR*, *ALK receptor tyrosine kinase* (*ALK*), *ataxia-telangiectasia mutated* (*ATM*) or *phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha* (*PIK3CA*), and tumor suppressor genes, such as the *tumor protein p53* (*TP53*), *liver kinase B1* (*LKB1*), or *Kelch-like ECH-associated protein 1* (*KEAP1*) [4–11].

Poly (ADP-ribose) polymerases (PARPs) are a family of 18 protein members that function as catalytic enzymes by adding ADP-ribose polymers to lysine residues of themselves and target proteins, a process termed poly (ADP-ribosyl)ation (PARylation). Among the proteins of the PARP family, PARP-1 and -2 are abundant nuclear enzymes involved in DNA damage repair, which involves binding to DNA breaks and facilitating the localization of repair enzymes, such as breast cancer 1/2 (BRCA1/2), to the sites of DNA damage [12,13]. Olaparib, rucaparib, niraparib, and talazoparib targeting PARP1/2 have been approved by the United States Food and Drug Administration (FDA) for the treatment of breast or ovarian cancer in patients harboring HR mutations that induce synthetic lethality in the *BRCA1* or *BRCA2* gene.

Evidence is accumulating that PARP inhibitors (PARPi) have therapeutic efficacy in cancer cells with high genomic instability by inducing synthetic lethality of cells with deficient or insufficient DNA repair [14–16]. Briefly, in this scenario, IR, or radiotherapy or cytotoxic chemotherapeutic agents that induce severe DNA damage could lead to insufficient DNA repair in targeted tumor cells. Consecutively, cells that adopt the "BRCAness" state could be treated with PARP inhibitor (PARPi) [17–20].

We have previously identified a potential novel PARPi, termed *N*-(3-(hydroxycarbamoyl)phenyl) carboxamide (designated KJ-28d). KJ-28d inhibited PARP-1/2 activities and displayed significant antitumor activity in human ovarian cancer *BRCA1*-deficient (*BRCA1* mutation at 5564G>A) SNU-251 cells [21]. In this study, we further investigated the antitumor activity of KJ-28d in *BRCA*-proficient cell lines, as well as the combination of KJ-28d and DNA damage-inducing radiotherapy or cytotoxic chemotherapeutics in human NSCLC cells.
