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Despite the development of advanced therapeutic regimens such as molecular targeted therapy and immunotherapy, the 5-year survival of patients with lung cancer is still less than 20%, suggesting the need to develop additional treatment strategies. Here we show the efficacy and biological mechanism of a novel antitumor agent, NCT compound. NCT compound exhibited significant inhibitory effects on the viability and colony formation of non-small cell lung cancer (NSCLC) cells and those carrying resistance to chemotherapy by inducing apoptosis. NCT compound markedly suppressed the migration of NSCLC cells. Consistently, NCT compound significantly suppressed tumor growth in a xenograft model. NCT compound showed minimal effects on the viability of normal cells and no overt toxic effects in mice, suggesting minimal toxicity of NCT compound. Further mechanistic studies revealed that NCT compound downregulated the activation of signaling pathway associated with cell proliferation and survival and the expression of epithelial-mesenchymal transition (EMT)-related markers. These results suggest the potential of NCT compound as an antitumor agent. Citation Format: Seung Yeob Hyun, Huong Thuy Le, Young-Sik Yong, Hye-Young Min, Jeewoo Lee, Ho-Young Lee. Development of a novel antitumor agent NCT compound for the treatment of non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4806.

Solid malignant tumors are composed of heterogeneous populations of cancer cell, including cancer stem-like cells (CSCs), a specialized cell population characterized by the functional properties of self-renewal and have a potential to differentiate into various cancer subtypes. CSCs contribute to tumor recurrence, metastasis, and drug resistance, affecting efficacy of anticancer therapies. However, treatment strategies specifically targeting CSCs are limited, because current chemotherapeutic drugs mainly kill the bulk of sensitive cancer cells, leaving behind CSCs. These remaining CSCs are the main cause of cancer relapse and drug resistance. Hence, development of novel compounds eradicating CSCs are crucial for effective anticancer therapies. To identify novel CSC-targeting anticancer drugs, we have set-up a reporter system based on promoter activities of CSC markers that allows a standardized identification of CSCs. By using the reporter system, we screened a large natural products chemical library consisting 452 compounds with diverse chemical entity. And we selected 4 compounds. To further assess the inhibitory effect of these 4 compounds, we used sphere-forming assay with NSCLC cell lines. Through these processes, we finally chose Compound E. We found that treatment with Compound E significantly reduced the subpopulation of NSCLC CSC. We confirmed the inhibitory effects of Compound E on NSCLC CSCs by performing sphere formation analysis and flow cytometry-based ALDH detection assay. Treatment with Compound E also suppressed the viability and colony-forming abilities of NSCLC cells (non-CSCs) and their sublines carrying acquired chemoresistance by inducing apoptosis. In line with these in vitro results, orally administered Compound E significantly suppressed the growth of xenograft tumors derived from both NSCLC cell lines and patient-derived tumor tissues. To determine the tumor forming capacity of tumor cells derived from the vehicle or Compound E-treated mice, we carried out a limiting dilution tumor-propagating assay. NOD/SCID mice were transplanted with tumor cells over a range from doses unable to initiate tumor growth to dose that initiated tumor formation. Tumor cells derived from Compound E-treated mice displayed reduced tumor forming capacity compared to vehicle treated mice. Mechanistically, Compound E disrupted Hsp70 function by binding to the ATP-binding pockets of Hsp70. These data collectively unveil the potential of Compound E as a natural Hsp70 inhibitor targeting both CSC and non-CSC populations of NSCLC. Citation Format: Seung Yeob Hyun, Huong Thuy Le, HongLan Pei, Simin Chun, Hye-Young Min, Suckchang Hong, Ho-Young Lee. Natural compound E targets both lung cancer stem and non-cancer stem cells by disrupting HSP70 function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1862.

Cancer stem-like cells (CSCs) contribute to tumor recurrence and chemoresistance. Hence, strategies eradicating CSCs are crucial for effective anticancer therapies. Here, we demonstrate transcriptional upregulation of the heat shock proteins (Hsp90 and Hsp70) and their co-chaperones and enhanced activities of the Hsp system in both non-CSCs and CSCs in non-small cell lung cancer (NSCLC) cells. Genetic and pharmacologic strategies targeting Hsps eliminated both CSCs and non-CSCs of NSCLC, suggesting the functional role of the Hsp system in the two populations in NSCLC. We further identified Compound A, a natural product-derived compound, as a novel Hsp70 inhibitor eliminating both the CSC and non-CSC populations in NSCLC. Compound A inhibited the sphere-forming ability of NSCLC CSCs by inducing apoptosis. Compound A also suppressed the viability and colony-forming abilities of NSCLC cells (non-CSCs) and their sublines carrying acquired chemoresistance by inducing apoptosis with minimal toxicity in normal cells derived from various organs. Mechanistically, Compound A disrupted Hsp70 function by binding to the ATP-binding pockets of Hsp70. These data suggest the rationale to target the Hsp system for controlling both CSCs and non-CSCs in NSCLC and the potential of Compound A as a natural Hsp70 inhibitor to eliminate the two populations with limited toxicities. Citation Format: Seung Yeob Hyun, Huong T. Le, Jaebeom Cho, Hye-Young Min, Ho-Young Lee. A natural product-derived Compound A effectively targets both cancer stem and non-stem cells in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2677.