bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 7150: Molecular insights into the oncogenic influence between mutant HER3, mutant KRAS, and their synergistic interplay in colorectal cancer pathogenesis
Authors: Kilroy Mary K. , Park Briley , Mishra Rosalin , Feroz Wasim , Wischmeier Cecilia , Garrett Joan T. 
Published: March 2024

Abstract
Colorectal cancer (CRC) is a disease of the colon and rectum that will claim about 52,550 American lives in 2023. In recent years, more attention has been paid to HER2 and HER3’s roles in colorectal cancers, as they may cause resistance to targeted therapies. We are investigating the role of naturally co-occurring HER3 and KRAS mutations in colorectal cancer, as about 6% of all colorectal cancers contain a HER3 mutation and 41% contain a KRAS mutation. We have observed that there is a statistically significant co-occurrence of HER3 and KRAS mutations in CRCs while there is mutual exclusivity with mutations in EGFR or HER4 and mutant KRAS in CRC examining 6791 samples from 17 studies. There is a tendency for co-occurrence with HER2 and KRAS mutations that is not statistically significant in these CRC tumor samples. We have found that genetic knockdown of both KRAS and HER3 with siRNA targeting KRAS and HER3 in the CRC cell line SNU-407 (HER3V104M, KRASG12D) results in a statistical reduction in cell proliferation in comparison to genetic knockdown with only KRAS or HER3. Using the SW620 CRC cell line (HER3WT, KRASG12V) as a comparison, we have observed that knocking down HER3 using siRNA had no effect on cell proliferation whereas KRAS knockdown reduced proliferation and the combination showed no statistical difference compared to knocking down only KRAS. Additionally, we have found that there is a striking increase in total HER3 levels in SNU-407 cells when treated with the KRASG12D inhibitor MRTX1133. This feedback loop could limit the efficacy of the KRAS inhibitor. We wished to delineate mutant HER3’s binding partner(s) as HER3 is kinase impaired. Strikingly, we have found that EGFR immunoprecipitates with HER3 in SNU-407 cells. We are expanding our studies to CRC patient derived xenografts (PDXs) with co-occurring HER3 and KRAS mutations and have generated patient derived organoids from these PDXs. Ongoing studies are determining if there is a synergistic relationship with KRAS inhibitors and HER family inhibitors including a HER3 antibody-drug conjugate. Our findings may present a new paradigm for targeted combination therapies in colorectal cancer with the eventual goal of increased overall patient survival.
Citation Format: Mary K. Kilroy, Briley Park, Rosalin Mishra, Wasim Feroz, Cecilia Wischmeier, Joan T. Garrett. Molecular insights into the oncogenic influence between mutant HER3, mutant KRAS, and their synergistic interplay in colorectal cancer pathogenesis [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 7150.
Abstract 7194: Targeting AXL and MCL-1 to eradicate lazertinib tolerance in EGFR-mutated NSCLC cells
Authors: Yamada Tadaaki , Matsui Yohei , Takayama Koichi 
Published: March 2024

Abstract
Lazertinib, a novel third-generation EGFR-tyrosine kinase inhibitor, has shown marked efficacy in patients with EGFR-mutant lung cancer. However, after various periods of therapeutic intervention, most patients eventually acquire resistance to lazertinib. A potential therapeutic approach to address this clinical issue is to overcome the initial drug resistance mechanism. To determine the underlying adaptive lazertinib resistance mechanisms, we evaluated signal transduction, cell apoptosis, and drug sensitivity in mutant EGFR-expressing non-small cell lung cancer (NSCLC) cells treated with lazertinib. The siRNA screening assay demonstrated that AXL knockdown significantly inhibited cell viability in the presence of lazertinib, indicating that AXL activation contributes to lazertinib resistance. However, long-term culture with a combination of lazertinib and AXL inhibitors eventually led to the proliferation of residual cells and increased MCL-1 expression, which was mediated by the nuclear translocation of the transcription factor YAP. Cell-based assays showed that triple therapy with an MCL-1 or YAP inhibitor, in combination with EGFR-TKI lazertinib, an AXL inhibitor, significantly reduced cell viability and increased apoptosis. These results demonstrate that AXL and YAP/MCL-1 signals contribute to the adaptive lazertinib resistance in EGFR-mutant NSCLC cells, suggesting that the initial dual inhibition of AXL and YAP/MCL-1 might be highly effective in eliminating lazertinib-resistant cells.
Citation Format: Tadaaki Yamada, Yohei Matsui, Koichi Takayama. Targeting AXL and MCL-1 to eradicate lazertinib tolerance in EGFR-mutated NSCLC 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 7194.
Abstract 7203: Anti-HDGF antibody attenuates the rise of resistance to EGFR tyrosine kinase inhibitor in NSCLC patient-derived xenograft tumors
Authors: Zhou Cindy Q. , Li Ariel , Ri Kaoru , Sultan Ahmed , Ren Hening 
Published: March 2024

Abstract
Mutant epidermal growth factor receptor (EGFR), a major oncogenic driver in non-small cell lung cancer (NSCLC), is found in the tumors of 15% (western countries) to 50% (Asian countries) of patients. EGFR-targeted therapy using tyrosine kinase inhibitors (TKIs) is a standard of care for those patients who developed metastatic or recurrent diseases. However, despite having an 80% initial response rate, most patients had partial tumor regression and their disease would progress when acquired resistance emerges. Thus, developing more effective treatment is an unmet need. The clinical response of these patients can be recapitulated in mouse models of patient-derived xenograft (PDX) tumor bearing sensitizing EGFR mutations. In this study, treating established PDX tumors with osimertinib, a third generation EGFR TKI, induced partial tumor regression (50% to 70% size reduction from baseline) followed by progression with a median progression-free survival (PFS) of 26 to 28 days. Interestingly, co-administering an antibody against hepatoma-derived growth factor (HDGF) with osimertinib resulted in enhanced tumor regression (98% to 100% size reduction from baseline) which translated into significantly extended animal survival with a median PFS of 103 or 135 days. Immunohistochemical and western blot examination of tumors collected at different treatment timepoints indicated that AKT/mTOR and MAPK pathways were reactivated after initial suppression in TKI monotherapy arm despite persistent EGFR inhibition. Since AKT/mTOR and MAPK pathways are key survival and proliferative signaling pathways, their reactivation can promote TKI tolerance of tumor cells and the emergence of TKI resistance. However, blocking HDGF attenuated the reactivation of these pathways which could partially explain the enhanced efficacy of osimertinib plus anti-HDGF antibody combination treatment seen in this study. Our results suggest tumor-derived HDGF could play a crucial role in the rise of acquired resistance to osimertinib. Identifying the exact cells and molecular pathways utilized by HDGF to promote tumor cell tolerance to TKI will help us understand how TKI sensitive tumor cells survive EGFR blockade and emerge as resistant cells.
Citation Format: Cindy Q. Zhou, Ariel Li, Kaoru Ri, Ahmed Sultan, Hening Ren. Anti-HDGF antibody attenuates the rise of resistance to EGFR tyrosine kinase inhibitor in NSCLC patient-derived xenograft tumors [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 7203.
Abstract 7205: PLK1 inhibition overcomes PARP inhibitor resistance in triple-negative breast cancer
Authors: Siraj Abdul K. , Poyil Pratheesh Kumar , Padmaja Divya , Parvathareddy Sandeep Kumar , Alobaisi Khadija , Begum Rafia , Almalik Osama , Al-Dayel Fouad , Al-Kuraya Khawla S. 
Published: March 2024

Abstract
Patients with aggressive breast cancer (BC) subtypes usually do not have favorable prognosis despite improvements in treatment modalities. These cancers remain a major cause of morbidity and mortality in women globally. This has fostered a major effort to discover actionable molecular targets to treat these patients. Polo-like Kinase (PLK1) is one of these molecular targets that are under comprehensive investigation for the treatment of such tumors. However, its role in the pathogenesis of BC from Middle Eastern ethnicity has not been explored. Therefore, we examined the expression of PLK1 protein in a large cohort of more than 1500 Middle Eastern ethnicity BC by immunohistochemistry. Correlation with clinico-pathological parameters and the prognosis was performed. PLK1 overexpression was observed in 27.4% of all BC and was significantly associated with aggressive clinico-pathological markers. The antitumor effect of PLK1 and PARP inhibitors either alone or in combination was tested in two BRCA mutated, and one BRCA proficient TNBC cell lines. We showed that combined inhibition significantly reduced cell survival and induced apoptosis in TNBC cell lines. Furthermore, our data suggest that PLK1 inhibition overcomes PARP inhibitor resistance in TNBC cell lines. These findings would pave the way to explore the future use of PLK1 inhibitors in the clinical setting of PARPi-resistant patients.
Citation Format: Abdul K. Siraj, Pratheesh Kumar Poyil, Divya Padmaja, Sandeep Kumar Parvathareddy, Khadija Alobaisi, Rafia Begum, Osama Almalik, Fouad Al-Dayel, Khawla S. Al-Kuraya. PLK1 inhibition overcomes PARP inhibitor resistance in triple-negative breast 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 7205.
Abstract 7218: Venetoclax triggers apoptosis and augments the effectiveness of doxorubicin against acute myeloid leukemia cells
Authors: Aloudat Osama , Al Odat Omar S. , Budak-Alpdogan Tulin , Jonnalagadda Subash , Chen Yong , Pandey Manoj 
Published: March 2024

Abstract
Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the clonal proliferation of immature blast cells in the peripheral blood and bone marrow. AML is the second most common type of childhood leukemia, and 50% to 60% of relapses occur within the first year of diagnosis. Chemotherapy side effects and resistance are becoming major clinical issues. Although anthracyclines are one of the most commonly used induction regimens for children with AML in the United States, clinicians avoid them due to adverse effects and clinical resistance issues. To address this clinical issue, we are looking for a novel AML approach to boost the usage of anthracyclines. Since Bcl-2 protein overexpression in AML is related to uncontrolled growth, poor prognosis, and chemoresistance. Multiple clinical trials have suggested combining venetoclax (a selective Bcl-2 inhibitor) with well-established medicines to boost efficacy and overcome resistance. We suggest that inhibiting Bcl-2 is a feasible strategy for increasing the use of anthracycline medicines. We proposed combining doxorubicin and venetoclax as an alternative approach for AML patients. In a panel of three AML cell lines, Kusami-1, U937, and THP-1, our western blot revealed that Kusami-1 had the highest expression of Bcl-2 proteins. Surprisingly, venetoclax causes Kusami-1 cell death and increases the efficacy of doxorubicin in a dose-dependent manner, suggesting that utilizing a lower clinical standard dose may avoid major adverse effects such as cardiotoxicity. Furthermore, the Annexin V Apoptosis Detection Kit indicated that venetoclax coupled with doxorubicin synergistically promoted total apoptosis in Kusami-1 cells. The combination medication shown promising and synergistic in vitro anti-leukemic action against AML cell lines and represents a potentially viable treatment option for AML patients. Future research will use the combination approach in AML cell lines, as well as in patient samples and in vivo experiments.
Citation Format: Osama Aloudat, Omar S. Al Odat, Tulin Budak-Alpdogan, Subash Jonnalagadda, Yong Chen, Manoj Pandey. Venetoclax triggers apoptosis and augments the effectiveness of doxorubicin against acute myeloid leukemia 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 7218.
Abstract 7223: A triplet therapeutic strategy targeting MEK, BCL-XL, and EGFR, for KRAS-mutant pancreatic ductal adenocarcinoma
Authors: Tushoski-Alemán Gerik W. , Crespin Alexandra J. , Oguejiofor Chibeze J. , McKean Jordan A. , Herremans Kelly M. , George Thomas J. , Allegra Carmen J. , Hughes Steven J. , Han Song 
Published: March 2024

Abstract
KRAS mutations drive over 90% of pancreatic cancers, but KRAS has been proven difficult to target. Downstream of KRAS, MEK inhibition in combination with BCL-XL inhibition is synthetically lethal and an effective treatment for gynecologic, but not colorectal malignancies. Like colorectal cancer, pancreatic cancer often exhibits aberrant HER/EGFR activity. We hypothesized that a triplicate regimen targeting MEK, BCL-XL, and EGFR/HER would be effective for pancreatic cancer. Trametinib (MEK inhibitor), Afatinib (pan-EGFR/HER inhibitor), and Navitoclax (BCL-XL inhibitor); or DT2216 (a BCL-XL/BCL-1 proteolysis targeting chimera, PROTAC) were explored using various combinatorial strategies. These drug combinations were tested using four primary human pancreatic cancer cell lines using live cell imaging (Incucyte) and an in vivo murine model. Group comparisons were analyzed using one-way ANOVAs, and adjusted p-values &lt;0.05 were considered significant. We observed that no single-agent treatments were effective. MEK inhibition plus anti-BCL-XL (Trametinib + Navitoclax or Trametinib + DT2216) demonstrated efficacy in one of the four cell lines. We noted synergistic effects on reduced cell growth and increased cell death when EGFR/HER inhibition was included by the administration of Afatinib. The triplet combination resulted in synergistic effects in three of four cell lines with Navitoclax and four of four cell lines with DT2216 (q&lt;0.05). This effect was confirmed with DT2216 inhibition of BCL-XL in an in-vivo murine model. In conclusion, our study shows that a combinatory strategy targeting MEK, BCL-XL, and pan-EGFR/HER receptor kinase shows significant synergistic effects in pancreatic cancer. Clinical trials that assess the efficacy and safety of this strategy for patients with KRAS-mutant pancreatic cancer are warranted. Our data also suggests that novel KRAS inhibitors as monotherapy are likely to fail.
Citation Format: Gerik W. Tushoski-Alemán, Alexandra J. Crespin, Chibeze J. Oguejiofor, Jordan A. McKean, Kelly M. Herremans, Thomas J. George, Carmen J. Allegra, Steven J. Hughes, Song Han. A triplet therapeutic strategy targeting MEK, BCL-XL, and EGFR, for KRAS-mutant pancreatic ductal adenocarcinoma [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 7223.
Abstract 7328: Relationship between PIN3 16bp duplication of TP53 and HPV in HIV women in Mali
Authors: Maiga Mamoudou , Diakite Brehima , Kassogue Yaya , Traore Ban , Kassogue Oumar , Kamate Bakarou , Traore Cheick B. , Holl Jane L. , Hou Lifang 
Published: March 2024

Abstract
Background: TP53 polymorphisms can influence the immune response to HPV, affecting TP53's role in cell cycle regulation and apoptosis, crucial for controlling HPV infection and preventing cancer.
Objective: Explore the link between TP53 PIN3 16-bp duplication and HPV infection in HIV-positive Malian women.
Methods: This study explored the link between PIN3 16-bp duplication polymorphism of TP53 and HPV infection in 50 HIV-positive women in Mali. Data included surveys, self-sampled vaginal swabs, and blood collection. HPV typing used GeneXpert, and PIN3 genotyping utilized AS-PCR.
Results: Participants, primarily &gt;30 years (92%), had a mean age of 43.30 ± 10.332 years. HPV prevalence was 36%, with P3 being the most common subtype (30.8%). PIN3 genotypic frequencies were A1A1 (50%), A1A2 (34%), and A2A2 (10%). History of sexually transmitted infections correlated with higher mutation rates (37.8% A1A2, 10.8% A2A2). A2A2 genotype prevalence was higher in HIV-positive women with specific HPV subtypes (P5, P4, HPV16, P3, P18/45). A1A2 genotype was observed in 60% of HPV subtype P3 cases and 20% of P4 and P18/45 cases.
Conclusion: These results suggest a link between TP53 gene polymorphisms and susceptibility to different HPV subtypes in HIV-positive women, warranting further research into their functional implications and impact on HPV-related diseases in this population.
Keywords: TP53 polymorphism, HPV, HIV, Malian population
Citation Format: Mamoudou Maiga, Brehima Diakite, Yaya Kassogue, Ban Traore, Oumar Kassogue, Bakarou Kamate, Cheick B. Traore, Jane L. Holl, Lifang Hou. Relationship between PIN3 16bp duplication of TP53 and HPV in HIV women in Mali [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 7328.
Abstract 7347: A transcriptome correlation network analysis of the high grade serous ovarian tumor immune microenvironment
Authors: Carey Kaylin M. , Dammer Eric B. , Young Corey , Singh Rajesh , Griffen Ti'ara , Lillard James W. 
Published: March 2024

Abstract
High Grade Serous Ovarian Cancer (HGSOC) affects many women and is the most common and lethal histopathological type of ovarian cancer. The molecular subtypes delineated by TCGA–mesenchymal, proliferative, immunoreactive, and differentiated subtypes, offer a sophisticated and innovative framework for HGSOC classification. These subtypes not only provide a detailed molecular characterization but also contribute to understanding the HGSOC Tumor Immune Microenvironment (TIME), comprised of both immune and tumor cells. The interplay within the TIME significantly influences pro- or anti-tumor responses, creating an important link between molecular landscape and dynamic immune-tumor interactions. Currently, there is a lack of understanding for the key drivers of clinical outcomes, molecular phenotypes, and diagnostic biomarkers for HGSOC. Here, we answer the question, does immune cell type, and proportion, drive clinical and molecular subtyping of primary HGSOC? Primary ovarian tumor samples from The Cancer Genome Atlas, TCGA (n=358) samples were collected and RNA-sequenced. FPKM values were used to construct the Weighted Gene Correlation Network Analysis (WGCNA), Gene Ontology (GO) and Proportion Estimations of Immune and Cancer cells (EPIC). Enrichment of HGSOC network module overlaps using a Fischer Exact Test were used to identify novel components of HGSOC progression that were significantly associated with clusters of highly correlated gene expression profiles, HGSOC stage, grade, and molecular phenotypes. We show genes associated with T cell proliferation (CD84) and B cell regulation (CD37), epithelial to mesenchymal transition (DOCK2), adaptor proteins present in T cells and myeloid cells (LCP2), inflammatory and metabolic signaling modulators (AIF1,CD53, SASH3), immunosuppressors of T lymphocytes and dendritic cells (FGL2), cell proliferation (PI3K) and relevant tertiary lymphoid structure gene (TNFAIP8L2) significantly correlated with HGSOC progression in both estimated tumor and proportions of immune cells. Future studies aim to confirm phosphorylation cascades associated with the aggressive molecular phenotypes of HGSOC and immune cell pathobiology.
Citation Format: Kaylin M. Carey, Eric B. Dammer, Corey Young, Rajesh Singh, Ti'ara Griffen, James W. Lillard. A transcriptome correlation network analysis of the high grade serous ovarian tumor immune microenvironment [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 7347.
Abstract 7355: Integration analysis of lncRNAs and R-loops in 3D genome organization and gene regulation in the cancer genome
Authors: Wang Shengyuan , Wang Zhenjia , Wang Yuh-Hwa , Li Hui , Stukenburg Peter Todd , Zang Chongzhi 
Published: March 2024

Abstract
Existing evidence shows that some long non-coding RNAs (lncRNAs) can recruit chromatin regulators and form R-loops to mediate CCTCC-binding factor (CTCF) binding at topologically associated domain (TAD) boundaries to activate transcription of target genes. However, it remains unclear to what extent such lncRNA-dependent chromatin organization events occur genome-wide in normal and cancer cells. By curated public data of lncRNA, CTCF, RAD21 profiles and integrative analysis of multi-omics data using innovative computational approaches, we investigated global associations of lncRNAs and R-loops with activities of transcription factors and chromatin regulators in gene expression regulations across multiple human cell types. We developed a comprehensive computational pipeline for cross-cell-type analysis of lncRNA and protein-coding gene expression profiles and transcription factor binding profiles. We identified a total of 542 candidate genomic regions where lncRNAs play a pivotal role in regulating target genes by facilitating CTCF/cohesin binding. R-loops are enriched at CTCF/cohesin binding sites, suggesting their potential contribution to CTCF binding. Additionally, our findings underscore the significant cell-type specificity of CTCF binding patterns across the genome. This work adds knowledge to cancer genome organization and gene regulation, and builds foundations for further functional and mechanistic studies of lncRNAs and R-loops in the human genome.
Citation Format: Shengyuan Wang, Zhenjia Wang, Yuh-Hwa Wang, Hui Li, Peter Todd Stukenburg, Chongzhi Zang. Integration analysis of lncRNAs and R-loops in 3D genome organization and gene regulation in the cancer genome [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 7355.