bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4568: Rational targeting of BCL-xL and/or mTOR enhance the efficacy of KRASG12D inhibitor in pancreatic cancer
Authors: Khan Sajid , Cao Lin , Vudhata Vignesh , Yang Yang , Zhang Peiyi , Zheng Guangrong , Trevino Jose G. , Zhou Daohong 
Published: March 2024

Abstract
Background: Pancreatic cancer (PaCa) is a highly aggressive malignancy with a very low five-year survival rate secondary to late diagnosis, limited treatment options and resistance to existing therapies. While the emergence of mutant-selective KRASG12D (G12D) inhibitors brings promise for treating PaCa patients carrying these mutations, their effectiveness as single agents is expected to be limited as evident from the clinical efficacy of KRASG12C inhibitors.
Experimental Design: First, multiple G12D-mutated PaCa cell lines were treated with a G12D inhibitor (MRTX1133) and subjected to immunoblot analysis for the expression of KRAS effectors and BCL-2 family proteins. Next, a proteolysis-targeting chimera (PROTAC)-based platelet-sparing BCL-xL degrader (DT2216) and/or an mTOR inhibitor (everolimus) were evaluated in combination with MRTX1133 for viability, clonogenicity and apoptosis. Subsequently, mechanistic investigations were carried out using immunoblotting, senescence-associated β-galactosidase staining and qPCR. Finally, therapeutic efficacy and safety of the combinations were evaluated in cell-derived and patient-derived xenograft models.
Results: MRTX1133 treatment creates apoptotic vulnerabilities by inducing aberrations in BCL-2 family proteins, with elevated BIM levels and decreased NOXA levels, in G12D-mutated PaCa cells. Furthermore, DT2216 and everolimus were shown to release BIM and stabilize NOXA, respectively, and their combination with MRTX1133 synergistically killed G12D-mutated PaCa cells in vitro and caused significant tumor growth inhibition or regression compared to single agents in vivo. Additionally, MRTX1133 treatment led to induction of senescence in a fraction of PaCa cells. These senescent cells were found to be dependent on BCL-xL and MCL-1 for their survival and were effectively killed with a combination of DT2216 and everolimus through BCL-xL degradation and NOXA-mediated MCL-1 inhibition, respectively.
Conclusions: Our findings suggest that the single agent efficacy of MRTX1133 is limited due to apoptosis inhibition and complimentary senescence induction, and therefore its combination with DT2216 and/or everolimus is synergistic, which can potentially overcome resistance, by enhanced apoptosis and clearance of senescent cells.
Citation Format: Sajid Khan, Lin Cao, Vignesh Vudhata, Yang Yang, Peiyi Zhang, Guangrong Zheng, Jose G. Trevino, Daohong Zhou. Rational targeting of BCL-xL and/or mTOR enhance the efficacy of KRASG12D inhibitor in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4568.
Abstract 4581: Identifying class 1 HDACs as a vulnerability for aggressive uveal melanoma
Authors: Yenisehirli Gulum , Zuniga Ashley , Rodriguez Sara , Adis Emily V. , Quintana Gabriela , Borges Sebastian , Lopez Sofia , Lopez Kassandra , Braun Steffanie , Volmar Claude H. , Harbour J. W. , Kurtenbach Stefan 
Published: March 2024

Abstract
Uveal melanoma (UM) is the most common primary intraocular cancer in adults, with a strong propensity to metastasize, primarily to the liver. Metastatic UM is notoriously unresponsive to existing therapies, rendering it almost uniformly lethal. Virtually all UM tumors have activating mutations in the Gq signaling pathway, predominantly in GNAQ/11, and around half of tumors have additional loss-of-function mutations in the tumor suppressor BAP1. Mutations in the epigenetic modulator BAP1 are the most significant clinical marker of metastatic risk. The limited efficacy of current treatment options necessitates an urgent exploration of novel therapeutic approaches to improve patient prognosis. Thus, we conducted a large epigenetic compound library screen with the currently most well characterized, focused epigenetic library available, which consisted of 960 potent, cell permeable, medically active, epigenetic-directed small molecule modulators (TargetMol, L1200). We screened BAP1-mutant as well as BAP1-wildtype uveal melanoma cell lines and followed up with comprehensive dose-response and synergy tests. Our lead compounds were highly efficient in reducing viability of UM cells. We find that inhibitors with high specificity for class 1 HDAC inhibition are especially cytotoxic to UM cells. Together, our results reveal a possible mechanism of interfering with UM progression and identify lead compounds to be tested in clinical trials.
Citation Format: Gulum Yenisehirli, Ashley Zuniga, Sara Rodriguez, Emily V. Adis, Gabriela Quintana, Sebastian Borges, Sofia Lopez, Kassandra Lopez, Steffanie Braun, Claude H. Volmar, J. W. Harbour, Stefan Kurtenbach. Identifying class 1 HDACs as a vulnerability for aggressive uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4581.
Abstract 4590: Antitumor effects of histone deacetylase inhibitors on breast cancer cell viability and mammosphere formation
Authors: Tehrani Golnaz Asaadi , Kubick Becca , Datta Meenal 
Published: March 2024

Abstract
Histone deacetylases (HDACs) are overexpressed in various types of primary human cancer and have become attractive targets for cancer therapy. This study aimed to evaluate the cytotoxic properties of three HDAC inhibitors (suberoylanilide hydroxamic acid (SAHA, or Vorinostat), Valproic Acid (VPA) and CAY10603) and compare them to Paclitaxel (PTX), a chemotherapy agent used to treat Triple Negative Breast Cancers (TNBCs). In the present study, drug response in the MDA-MB-231, MDA-MB-468, and MCF-10A cell lines was evaluated by cell viability assays. Apoptosis and cell cycle distribution were analyzed by flow cytometry. Mammospheres generated from MDA-MB-231 and MDA-MB-468 breast cancer cells were also subjected to drug treatment; their response was assessed under both normoxic and hypoxic conditions.
We found that SAHA and CAY10603 inhibited breast cancer cell viability without significantly affecting MCF-10A cells. SAHA, CAY10603, and VPA all arrested a significant percentage of MDA-MB-231 cells at G2/M phase after 24h compared to controls. TNBC cells experienced an increase in both early and late apoptosis following treatment with the most effective concentrations of SAHA, CAY10603, and VPA (1.8µM, 2µM, and 0.4mM, respectively). SAHA proved to be the most effective drug for induction of apoptosis compared to the control, followed by CAY10603 (8.26% and 6%, 3.67%). In both TNBCs and mammospheres under hypoxic conditions, SAHA and CAY10603 down regulated HIF-1α expression significantly, but PTX did not. In contrast, VPA and PTX down regulated CTNNB1 gene expression.
This study indicates that epi-drugs exert an anti-tumor effect on TNBCs, suggesting a potential role for HDAC inhibitors as novel therapeutics for breast cancer patients.
Citation Format: Golnaz Asaadi Tehrani, Becca Kubick, Meenal Datta. Antitumor effects of histone deacetylase inhibitors on breast cancer cell viability and mammosphere formation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4590.
Abstract 4593: A synergy between MDM2 and AURKB pathways in driving cell cycle and cell survival in lung cancer cells
Authors: Natarajan Umamaheswari , Rathinavelu Appu 
Published: March 2024

Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide and non-small cell lung cancer (NSCLC) is the most prevalent type among lung cancers, contributing to the high mortality seen with this deadly disease. Despite aggressive treatments, the 5-year survival rate for lung cancer is only 23.7% in the United States. MDM2 and AURKB are two cancer-driving genes that are highly expressed in a broad range of cancer types including lung cancers. Furthermore, MDM2 overexpression can positively impact AURKB expression and contribute to oncogenesis and cancer progression. Therefore, blocking MDM2 with specific inhibitors has become a promising strategy for the restoration of p53 function that could be used for the treatment of different types of cancers including lung cancers. In this regard, both MDM2 and AURKB inhibitors have shown promising antitumor activity against NSCLC. Therefore, the main objective of this study was to understand the molecular mechanisms linking MDM2 and ARKB using RG7388, CM272, BMS-582949 (p38 inhibitor), and Ralimetinib (p38 inhibitor) in A549 and H460 lung cancer cells. We analyzed the individual or combination treatment effects of these drugs on epigenetic modifications, cell cycle arrest, and cell death mechanisms, using the in vitro experimental model. When RG7388 was used individually, or in combination with BMS-582949 or Ralimetinib, a significant increase in the cytotoxic effect was observed in A549 and H460 cells. Induction of cell cycle arrest by RG7388 in cancer cells was evidenced by elevated p21 expression levels. In addition, RG7388 and combination treatments in NSCLC cells showed significant upregulation of p53, p27, Bax, cleaved PARP, phospho-FOXO3a and down-regulation in DNMT3a, DNMT1, FOXM1, AURKB, CDC25, and CDK4 levels. It appears that during treatments with a combination of MDM2 with DNMT or p38 inhibitor, two pathways might be blocked simultaneously, which could lead to increased cancer cell death. RG7388 appears to induce cell death in a p21-dependent manner and CM272, BMS-582949, and Ralimetinib seem to induce cell death via a p21-independent manner by inhibiting a downstream pathway. However, further studies are needed to fully understand the intracellular link between MDM2 and AURKB that is disrupted by the anti-cancer agents used in our study. (This project was supported by the PFRDG Grant of Nova Southeastern University and by the Generous support from the Royal Dames of Cancer Research Ft. Lauderdale, FL)
Citation Format: Umamaheswari Natarajan, Appu Rathinavelu. A synergy between MDM2 and AURKB pathways in driving cell cycle and cell survival in lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4593.
Abstract 4597: RNA m1A methyltransferase TRMT61A induces MAPK/ERK signaling and is a therapeutic target in colorectal cancer
Authors: Zhang Xiaoting , Qin Na , Ji Fenfen , Su Hao , Chen Hongyan , Shang Haiyun , Chen Huarong 
Published: March 2024

Abstract
The widespread presence of N1-methyladenosine (m1A) modifications controls RNA metabolism and is pivotal to fundamental biological processes. However, the understanding of RNA m1A involved in cancer is still minimal. Here we reported the oncogenic role and the therapeutic targeting of RNA m1A methyltransferase TRMT61A in colorectal cancer (CRC). We observed consistent elevation of TRMT61A expression and RNA m1A levels in primary CRC tissues, which was significantly associated with poor patient survival in two independent cohorts (both P&lt;.001). CRISPR/Cas9 screenings revealed that TRMT61A is the most essential gene among m1A regulators. TRMT61A facilitates the growth and metastasis of CRC cells by increasing the stability of mRNA of crucial targets, such as ONECUT2, which leads to the activation of MAPK/ERK signaling in an m1A-dependent manner. Notably, depletion of ONECUT2 or inhibition of MAPK/ERK could abrogate the tumor-promoting role of TRMT61A, implying that TRMT61A induces ONECUT2-MAPK/ERK axis to facilitate CRC. Inhibiting TRMT61A with nanoparticle-encapsulated siTRMT61A or our recently identified small molecule compound PGG shows promising anti-CRC effects in vitro and in vivo. Together, our study reveals the promoting role of TRMT61A-induced m1A modification in MAPK/ERK signaling and highlights the potential of targeting TRMT61A as a promising therapeutic approach in CRC treatment.
Citation Format: Xiaoting Zhang, Na Qin, Fenfen Ji, Hao Su, Hongyan Chen, Haiyun Shang, Huarong Chen. RNA m1A methyltransferase TRMT61A induces MAPK/ERK signaling and is a therapeutic target in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4597.
Abstract 4651: A macrocyclic kinase inhibitor overcomes the compound mutations that cause the resistance to all approved EGFR inhibitors in EGFR-positive lung cancer
Authors: Katayama Ryohei , Uchibori Ken , Nishio Makoto , Fujita Naoya 
Published: March 2024

Abstract
EGFR mutant cancers account for 20-30 % of non-small cell lung cancers and show marked sensitivity to EGFR tyrosine kinase inhibitors (TKIs). However, the tumor almost inevitably relapses due to acquired resistance. To date, several EGFR-TKIs have been approved, and the third-generation EGFR-TKI, osimertinib, has been widely used both as first-line therapy and for patients with the EGFR-T790M mutation after 1st or 2nd generation EGFR-TKI therapy. However, the EGFR-T790M+C797S compound mutation confers resistance to all approved EGFR-TKIs. In our previous study, we experimentally demonstrated that brigatinib with anti-EGFR antibody was effective against osimertinib-resistant EGFR-C797S and EGFR-T790M+C797S mutants, and is currently undergoing clinical studies. However, the tumor would relapse because of the acquisition of additional resistance mutations. Here, we first demonstrated the binding mode of brigatinib to the EGFR-T790M/C797S mutant by crystal structure analysis and predicted brigatinib-resistant mutations through a cell-based assay, including N-ethyl-N-nitrosourea (ENU) mutagenesis. We found that clinically reported L718 and G796 compound mutations appeared, consistent with their proximity to the binding site of brigatinib, and brigatinib-resistant quadruple mutants, such as EGFR-activating mutation/T790M/C797S/L718M, were resistant to all clinically available EGFR-TKIs. BI-4020, a fourth-generation macrocyclic EGFR inhibitor plus anti-EGFR antibody, overcomes the quadruple and major EGFR-activating mutants in vitro and in vivo, but not the minor mutants such as L747P. Microsecond molecular dynamics simulations revealed the binding mode and affinity between BI-4020 and the EGFR mutants. This study identified potential therapeutic strategies using new-generation macrocyclic EGFR inhibitor to overcome the emerging resistance mutants.
Citation Format: Ryohei Katayama, Ken Uchibori, Makoto Nishio, Naoya Fujita. A macrocyclic kinase inhibitor overcomes the compound mutations that cause the resistance to all approved EGFR inhibitors in EGFR-positive lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4651.
Abstract 4674: Reserpine analog modulates transport function of ABCG2
Authors: Ohnuma Shinobu , Kokubo Shoji , Sugisawa Norihiko , Murakami Megumi , Hatsuzawa Yuuri , Kobayashi Minoru , Kajiwara Taiki , Suzuki Hideyuki , Karasawa Hideaki , Watanabe Kazuhiro , Doi Takayuki , Ambudkar Suresh V. , Kamei Takashi , Unno Michiaki 
Published: March 2024

Abstract
Backgrounds: Reserpine is an agent that is used for the treatment of hypertension. ABCG2 also known as breast cancer resistance protein (BCRP) is a member of the ABC transporters associated with multidrug resistance (MDR). Our high-throughput screening assay has revealed that reserpine analog inhibits transport function of ABCG2.
Aim: To investigate the effect of reserpine analog on ABCG2 function.
Results: Flow cytometry assay showed that reserpine analog blocked the efflux of Pheophorbide a (PhA: fluorescent substrate of ABCG2) from ABCG2-expressing HCT-116/BCRP colon cancer cells in a concentration-dependent manner. Furthermore, cell proliferation assay (MTS assay) revealed that 5 and 10 μM reserpine analog sensitized HCT-116/BCRP cells to SN38 with IC50 value 0.61 + 0.12 μM and 0.22 + 0.036 μM, respectively. Finally, reserpine analog did not stimulate ABCG2-mediated ATP hydrolysis, but rather inhibited it (concentration required for 50% inhibition = 2.7 μM), suggesting that reserpine analog might prevent conformational changes required for ATP hydrolysis.
Conclusion: Reserpine analog could be developed as a potent modulator to overcome ABCG2-mediated MDR in cancer cells.
Citation Format: Shinobu Ohnuma, Shoji Kokubo, Norihiko Sugisawa, Megumi Murakami, Yuuri Hatsuzawa, Minoru Kobayashi, Taiki Kajiwara, Hideyuki Suzuki, Hideaki Karasawa, Kazuhiro Watanabe, Takayuki Doi, Suresh V. Ambudkar, Takashi Kamei, Michiaki Unno. Reserpine analog modulates transport function of ABCG2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4674.
Abstract 470: AR-induced miRNA124-3p.2 suppresses the metastasis-promoting factor CCL2
Authors: Aoyama Shuhei , Izumi Kouji , Mizokami Atsushi 
Published: March 2024

Abstract
Objective: The standard treatment for advanced prostate cancer is androgen deprivation therapy that blocks androgen receptor (AR) signaling, but this therapy becomes ineffective within a few years, resulting in castration-resistant prostate cancer. We have previously shown that blockade of AR signaling induces CCL2 and activates cancer cells through an autocrine mechanism, but why AR blockade induces CCL2 secretion has not been elucidated. Micro RNAs (miRs) are endogenous non-coding RNAs that regulate the translation of various proteins. In this study, we investigated whether miRs are involved in CCL2 induction.
Subjects and Methods: We used miRNA PCR Plate Array and Target Scan (https://www.targetscan.org) to search for miRs that are controlled by AR and bind to and repress the CCL2 gene. We knocked down the AR of human prostate cancer cell lines LNCaP and C4-2B with siRNA (siAR) and examined the expression of target miRs and CCL2. siAR-transfected LNCaP and C4-2B were transfected with target miR mimic and CCL2 expression was examined. siAR-transfected LNCaP, C4-2B, and C4-2B were transfected with target miR mimic and CCL2 expression was examined. siAR-transfected LNCaP and C4-2B were transfected with target miR mimic and CCL2 expression was examined. The target miR mimic was introduced into them, and the changes in migration ability were evaluated.
Results: miR-124-3p.2 was extracted as a candidate from miRNA PCR Plate Array and Target Scan. miR-124-3p.2 expression was upregulated in both LNCaP and C4-2B when DHT was added and downregulated when CCL2 was added. In siAR LNCaP and C4-2B, the expression of CCL2 was decreased when miR-124-3p.2 mimic was introduced. Furthermore, in siAR-transfected LNCaP, C4-2B, the introduction of miR-124-3p.2 mimic suppressed the migration.
Conclusion: AR suppresses CCL2 via miR124-3p.2. miR124-3p.2-mediated regulation of CCL2 may be a new therapeutic target for advanced prostate cancer.
Citation Format: Shuhei Aoyama, Kouji Izumi, Atsushi Mizokami. AR-induced miRNA124-3p.2 suppresses the metastasis-promoting factor CCL2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 470.
Abstract 4724: Optimizing 500 pooled PRISM cell lines for a 10-day assay to elucidate viability effects and mechanism of action for slower-acting therapeutics
Authors: Ronan Melissa , Ip Blanche C. , Nguyen Ellen , Widocki Ursula , Sangpo Tenzin , Kalathungal Alvin , Diaz-Gallegos Nashielli , Fazio Anthony , Golabi Aydin , Naim Maha , George Ashish Bino , Liu YuhJong , Kocak Mustafa , Puram Rishi , Rees Matthew G. , Roth Jennifer 
Published: March 2024

Abstract
PRISM (Profiling Relative Inhibition Simultaneously in Mixtures), using DNA-barcoded cell lines cultured as ~25 cell line pools, has been an effective drug discovery screening platform to rapidly test large numbers of potential therapeutics on over 900 different cancer cell lines. However, the conventional 5-day assay may be too short to offer the resolution needed to identify the full cellular response for slower-acting therapeutics such as those directed against epigenetic pathways. Here, we describe development of the PRISM 10-day extended assay with ~500 adherent solid tumor cancer cell lines to overcome this challenge. We found that the ranges of cell line growth rates within the standard PRISM pools were too large and not amenable for a long-term assay beyond 6 days—after 10 days of growth, slower cell lines dropped below the limit of barcode detection as faster cell lines overtook the pools. We therefore regenerated pools to reduce the range of growth rates within a pool. We show that this re-pooling, coupled with seeding density optimization, enables recovery of &gt; 98% of cell lines at day 10 in vehicle-treated wells, with acceptable data variability. The average estimated number of cell doublings across our cell lines, 7, is significantly greater than the number of doublings in the PRISM standard 5-day assay (~3 doublings). Importantly, we observe greater drug effects on day 10 versus day 6 when cells are treated with slow-acting DNA methyltransferase inhibitors such as decitabine; this also results in increased sensitivity to identify cellular biomarkers underlying differential response. In summary, we have successfully engineered a PRISM 10-day assay in ~500 adherent cell lines, where the extended duration can be beneficial in elucidating the effects and mechanism of action for epigenetic drug candidates.
Citation Format: Melissa Ronan, Blanche C. Ip, Ellen Nguyen, Ursula Widocki, Tenzin Sangpo, Alvin Kalathungal, Nashielli Diaz-Gallegos, Anthony Fazio, Aydin Golabi, Maha Naim, Ashish Bino George, YuhJong Liu, Mustafa Kocak, Rishi Puram, Matthew G. Rees, Jennifer Roth. Optimizing 500 pooled PRISM cell lines for a 10-day assay to elucidate viability effects and mechanism of action for slower-acting therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4724.