Anticancer Therapeutic Target Research Articles

Homeostatic status of thyroid hormones and brain water movement as determinant factors in biology of cerebral gliomas: a pilot study using a bioinformatics approach.

The expression and localization of the water channel transporters, aquaporins (AQPs), in the brain are substantially modified in gliomas during tumorigenesis, cell migration, edema formation, and resolution. We hypothesized that the molecular changes associated with AQP1 and AQP4 in the brain may potentially be anticancer therapeutic targets. To test this hypothesis, a bioinformatics analysis of publicly available data from international consortia was performed. We used RNA-seq as an experimental strategy and identified the number of differential AQP1 and AQP4 transcript expressions in glioma tissue compared to normal brain tissue. AQPs genes are overexpressed in patients with glioma. Among the glioma subtypes, AQP1 and AQP4 were overexpressed in astrocytoma (low-grade glioma) and classical (high-grade glioma). Overall survival analysis demonstrated that both AQP genes can be used as prognostic factors for patients with low-grade glioma. Additionally, we observed a correlation between the expression of genes involved in the tyrosine and thyroid hormone pathways and AQPs, namely: PNMT, ALDH1A3, AOC2, HGDATP1B1, ADCY5, PLCB4, ITPR1, ATP1A3, LRP2, HDAC1, MED24, MTOR, and ACTB1 (Spearman's coefficient = geq 0.20 and p-value = ≤ 0.05). Our findings indicate that the thyroid hormone pathways and AQPs 1 and 4 are potential targets for new anti-tumor drugs and therapeutic biomarkers for malignant gliomas.

Mechanical activation and expression of HSP27 in epithelial ovarian cancer

Understanding the complex biomechanical tumor microenvironment (TME) is of critical importance in developing the next generation of anti-cancer treatment strategies. This is especially true in epithelial ovarian cancer (EOC), the deadliest of the gynecologic cancers due to recurrent disease or chemoresistance. However, current models of EOC progression provide little control or ability to monitor how changes in biomechanical parameters alter EOC cell behaviors. In this study, we present a microfluidic device designed to permit biomechanical investigations of the ovarian TME. Using this microtissue system, we describe how biomechanical stimulation in the form of tensile strains upregulate phosphorylation of HSP27, a heat shock protein implicated in ovarian cancer chemoresistance. Furthermore, EOC cells treated with strain demonstrate decreased response to paclitaxel in the in vitro vascularized TME model. The results provide a direct link to biomechanical regulation of HSP27 as a mediator of EOC chemoresistance, possibly explaining the failure of such therapies in some patients. The work presented here lays a foundation to elucidating mechanobiological regulation of EOC progression, including chemoresistance and could provide novel targets for anti-cancer therapeutics.

CBX2 Deletion Suppresses Growth and Metastasis of Colorectal Cancer by Mettl3-p38/ERK MAPK Signalling Pathway.

Colorectal cancer (CRC) seriously endangers human health owing to its high morbidity and mortality. Previous studies have suggested that high expression of CBX2 may be associated with poor prognosis in CRC patients. However, its functional role in CRC remains to be elucidated. Herein, we found that CBX2 overexpression in colorectal cancer tissue compared with adjacent tissues. Additionally, forest maps and the nomogram model indicated that elevated CBX2 expression was an independent prognostic factor in CRC. Moreover, we confirmed that the deletion of CBX2 markedly suppressed the proliferation and migration of CRC cells in vitro and in vivo. Furthermore, downregulation of CBX2 promotes CRC cell apoptosis and hinders the cell cycle. Mechanistically, our data demonstrated that deletion of CBX2 inhibited the MAPK signaling pathway by regulating the protein levels of Mettl3. In conclusion, our study demonstrated that CBX2 is a vital tumor suppressor in CRC and could be a promising anti-cancer therapeutic target.

Synthesis and biological evaluation of selenopyrimidine derivatives bearing thiazolyl moiety

The aim of this study is to explain how new thiazole and selenophene moieties were obtained from 2-amino-4-(4-methylthiazol-2-yl)selenophene-3-carbonitrile (3) and to assess the antioxidant and cytotoxic properties of these new compounds. Compound 3 is prepared and subjected to react with each of CS2, malononitrile in EtOH/TEA, ECA, a mixture of HCl and AcOH, formamide, formic acid, malononitrile in the presence of EtONa to give their corresponding selenopyrimidine and selenopyridine derivatives 4–10. Moreover, compound 3 reacted with thiourea, hydrazine hydrate, CS2 in NaOH/DMF, and phenyl isothiocyanate to afford selenolo[2,3-d]pyrimidines 11–17 and related compounds. The recently synthesized compounds were tested for their DPPH radical scavenging and cytotoxic properties against the HePG-2 and MCF-7 cell lines. Compounds 5 and 11 demonstrated potential radical scavenging activity, but compounds 5 and 6 exhibited the strongest cytotoxic action against the examined cell lines. According to molecular docking data, the compounds under research are intriguing candidates for the development of new anticancer therapeutic targets.

The Golgi Apparatus as an Anticancer Therapeutic Target.

Although the discovery of the Golgi apparatus (GA) was made over 125 years ago, only a very limited number of therapeutic approaches have been developed to target this complex organelle. The GA serves as a modification and transport center for proteins and lipids and also has more recently emerged as an important store for some ions. The dysregulation of GA functions is implicated in many cellular processes associated with cancer and some GA proteins are indeed described as cancer biomarkers. This dysregulation can affect protein modification, localization, and secretion, but also cellular metabolism, redox status, extracellular pH, and the extracellular matrix structure. Consequently, it can directly or indirectly affect cancer progression. For these reasons, the GA is an appealing anticancer pharmacological target. Despite this, no anticancer drug specifically targeting the GA has reached the clinic and few have entered the clinical trial stage. Advances in nanodelivery approaches may help change this scenario by specifically targeting tumor cells and/or the GA through passive, active, or physical strategies. This article aims to examine the currently available anticancer GA-targeted drugs and the nanodelivery strategies explored for their administration. The potential benefits and challenges of modulating and specifically targeting the GA function in the context of cancer therapy are discussed.

Phenotypic profiling of solute carriers characterizes serine transport in cancer

Serine is a vital amino acid in tumorigenesis. While cells can perform de novo serine synthesis, most transformed cells rely on serine uptake to meet their increased biosynthetic requirements. Solute carriers (SLCs), a family of transmembrane nutrient transport proteins, are the gatekeepers of amino acid acquisition and exchange in mammalian cells and are emerging as anticancer therapeutic targets; however, the SLCs that mediate serine transport in cancer cells remain unknown. Here we perform an arrayed RNAi screen of SLC-encoding genes while monitoring amino acid consumption and cell proliferation in colorectal cancer cells using metabolomics and high-throughput imaging. We identify SLC6A14 and SLC25A15 as major cytoplasmic and mitochondrial serine transporters, respectively. We also observe that SLC12A4 facilitates serine uptake. Dual targeting of SLC6A14 and either SLC25A15 or SLC12A4 diminishes serine uptake and growth of colorectal cancer cells in vitro and in vivo, particularly in cells with compromised de novo serine biosynthesis. Our results provide insight into the mechanisms that contribute to serine uptake and intracellular handling.

The association of claudin-18 and androgen receptor expression in prostatic carcinoma: an immunohistochemical study

BackgroundClaudin-18 (CLDN18) is a recently identified anticancer therapeutic target with promising results for various gastrointestinal malignancies. The role of CLDN18 in prostatic carcinoma has not been investigated. The aim of this study was to investigate CLDN18 and androgen receptor (AR) expression in prostatic carcinoma and to link these findings with other clinicopathological characteristics. This retrospective study was carried out on 120 cases of prostatic lesions, including 100 cases of prostatic carcinoma and 20 cases of benign prostatic hyperplasia. The immunohistochemical staining technique was used to evaluate the expression of both CLDN18 and AR in prostatic carcinoma in relation to clinicopathological parameters.ResultsCLDN18 expression was completely absent in benign prostatic tissue, while it was detected in the membrane of 30 (30%) of studied carcinoma cases, with a statistically significant difference (p = 0.046). In contrast to other variables, a statistically significant relationship was identified between CLDN18 expression and Gleason Grade group (p = 0.000), stage (p = 0.03), and nodal metastasis (p = 0.000). The expression of the androgen receptor was detected in the nucleus of 96 (96%) of the cancer cases under study, with no statistically significant difference between the studied groups (p = 0.427). A statistically significant relation was found between AR expression and Gleason Grade group (p = 0.03) and stage (p = 0.01), while no relation with other variables was detected. AR expression and CLDN18 expression were shown to be statistically significantly correlated (p = 0.002).ConclusionsCLDN18 was expressed in prostatic carcinoma and correlated with an adverse tumor outcome. CLDN18 may be regulated by AR. CLDN18 could be a candidate therapeutic marker for the treatment of prostatic carcinoma.

First-in-Human Study with Preclinical Data of BCL-2/BCL-xL Inhibitor Pelcitoclax in Locally Advanced or Metastatic Solid Tumors.

B-cell lymphoma-extra-large (BCL-xL) regulates apoptosis and is an attractive anticancer therapeutic target. However, BCL-xL inhibition also kills mature platelets, hampering clinical development. Using an innovative prodrug strategy, we have developed pelcitoclax (APG-1252), a potent, dual BCL-2 and BCL-xL inhibitor. Aims of this study were to characterize the antitumor activity and safety of pelcitoclax and explore its underlying mechanisms of action (MOA). Cell line-derived xenograft and patient-derived xenograft (PDX) models were tested to evaluate antitumor activity and elucidate MOA. Subjects (N = 50) with metastatic small-cell lung cancer and other solid tumors received intravenous pelcitoclax once or twice weekly. Primary outcome measures were safety and tolerability; preliminary efficacy (responses every 2 cycles per RECIST version 1.1) represented a secondary endpoint. Pelcitoclax exhibited strong BAX/BAK‒dependent and caspase-mediated antiproliferative and apoptogenic activity in various cancer cell lines. Consistent with cell-based apoptogenic activity, pelcitoclax disrupted BCL-xL:BIM and BCL-xL:PUMA complexes in lung and gastric cancer PDX models. Levels of BCL-xL complexes correlated with tumor growth inhibition by pelcitoclax. Combined with taxanes, pelcitoclax enhanced antitumor activity by downregulating antiapoptotic protein myeloid cell leukemia-1 (MCL-1). Importantly, pelcitoclax was well tolerated and demonstrated preliminary therapeutic efficacy, with overall response and disease control rates of 6.5% and 30.4%, respectively. Most common treatment-related adverse events included transaminase elevations and reduced platelets that were less frequent with a once-weekly schedule. Our data demonstrate that pelcitoclax has antitumor activity and is well tolerated, supporting its further clinical development for human solid tumors, particularly combined with agents that downregulate MCL-1.

Mechanism underlying the effect of Pulsatilla decoction in hepatocellular carcinoma treatment: a network pharmacology and in vitro analysis

BackgroundCurrently, hepatocellular carcinoma (HCC) is associated with a poor prognosis. Moreover, there exist limited strategies for treating HCC. Pulsatilla decoction (PD), a traditional Chinese medicine formula, has been used to treat inflammatory bowel disease and several cancer types. Accordingly, we explored the mechanism of PD in HCC treatment via network pharmacology and in vitro experiments.MethodsOnline databases were searched for gene data, active components, and potential target genes associated with HCC development. Subsequently, bioinformatics analysis was performed using protein–protein interaction and Network Construction and Kyoto Encyclopedia of Genes and Genomes (KEGG) to screen for potential anticancer components and therapeutic targets of PD. Finally, the effect of PD on HCC was further verified by in vitro experiments.ResultsNetwork pharmacological analysis revealed that 65 compounds and 180 possible target genes were associated with the effect of PD on HCC. These included PI3K, AKT, NF-κB, FOS, and NFKBIA. KEGG analysis demonstrated that PD exerted its effect on HCC mainly via the PI3K-AKT, IL-17, and TNF signaling pathways. Cell viability and cell cycle experiments revealed that PD could significantly inhibit cancer cell proliferation and kill HCC cells by inducing apoptosis. Furthermore, western blotting confirmed that apoptosis was mediated primarily via the PI3K-AKT, IL-17, and TNF signaling pathways.ConclusionTo the best of our knowledge, this is the first study to elucidate the molecular mechanism and potential targets of PD in the treatment of HCC using network pharmacology.

Uncovering the Contrasting Binding Behavior of Plant Flavonoids Fisetin and Morin Having Subsidiary Hydroxyl Groups (-OH) with HRAS1 and HRAS2 i-Motif DNA Structures: Decoding the Structural Alterations and Positional Influences.

Research on the interactions of naturally existing flavonoids with various noncanonical DNA such as i-motif (IM) DNA structures is helpful in comprehending the molecular basis of binding mode as well as providing future direction for the application and invention of novel effective therapeutic drugs. IM DNA structures have been identified as prospective anticancer therapeutic targets, and flavonoids are smaller molecules with a variety of health-promoting attributes, including anticancer activities. The extensive investigation comprising a series of techniques reveals the contrasting mode of the binding behavior of fisetin and morin with various IM DNA structures. We have discovered that structural alterations of hydroxyl groups located at different places of aromatic rings influence flavonoid's reactivity. This minor structural alteration appears to be critical for fisetin and morin's capacity to interact differentially with HRAS1 and HRAS2 IM DNA. Hence, fisetin appears to be an efficient ligand for HRAS1 and morin is considered to be an efficient ligand for HRAS2 IM DNA. This novel exploration opens up the possibility of employing the strategy for regulation of gene expression in cancerous cells. Our finding also reveals the flavonoid-mediated specific interaction with IM DNA while pointing toward tangible strategies for drug discovery and other essential cellular functions.

MiR-4284 Functions as a Tumor Suppressor in Renal Cell Carcinoma Cells by Targeting Glutamate Decarboxylase 1.

MicroRNAs (miRNAs) play a crucial role as oncogenic or tumor suppressors in the pathogenesis and progression of tumors. However, few studies have investigated the exact role of miR-4284 in renal cell carcinoma (RCC). We aimed to investigate the role of miR-4284 as a tumor suppressor in renal cancer cell lines. A498 and Caki-1 were transfected with miR-4284. The Cell Counting Kit-8, colony formation, apoptosis assays, and quantitative reverse transcription-polymerase chain reaction were used to evaluate tumor growth-inhibiting functions. The wound-healing, transwell, and sphere-formation assays were conducted to investigate tumorigenic characteristics. The potential target genes of miR-4284 were predicted and experimentally verified. A xenograft experiment was performed to estimate the tumor-growth-suppressive function of miR-4284. miR-4284 overexpression suppressed proliferation, induced apoptosis, and suppressed tumorigenic features of renal cancer cells. Glutamate decarboxylase 1 (GAD1) was directly targeted by miR-4284. A xenograft mouse model injected with Caki-1 cells transfected with miR-4284 showed significantly decreased tumor growth rate and volume. miR-4284 affected tumor growth, metastasis, and apoptosis of renal cancer cells in vitro and in vivo. These findings highlight the potential of miR-4284 as a target for anticancer miRNA therapeutics in RCC.

Small molecule, nanoparticle and liposomal strategies for LAT1-mediated chemotherapy delivery

LAT1 has become a popular target for anti-cancer therapeutics due to its role as a nutrient transporter and abundant expression in cancer cells. Although small molecule inhibition has been the major focus of LAT1-based chemotherapies, using LAT1-substrates as a carrier will allow delivery of known drugs to cells, improving their intracellular uptake and thus decreasing concentrations required to give the desired biological effect. This review highlights the current efforts in using LAT1-amino acid substrates as carriers for chemotherapeutic delivery.

Inhibition of Topoisomerases by Metal Thiosemicarbazone Complexes.

Topoisomerases, common targets for anti-cancer therapeutics, are crucial enzymes for DNA replication, transcription, and many other aspects of DNA metabolism. The potential anti-cancer effects of thiosemicarbazones (TSC) and metal-TSC complexes have been demonstrated to target several biological processes, including DNA metabolism. Human topoisomerases were discovered among the molecular targets for TSCs, and metal-chelated TSCs specifically displayed significant inhibition of topoisomerase II. The processes by which metal-TSCs or TSCs inhibit topoisomerases are still being studied. In this brief review, we summarize the TSCs and metal-TSCs that inhibit various types of human topoisomerases, and we note some of the key unanswered questions regarding this interesting class of diverse compounds.

Determining the mechanism of pulsatilla decoction for treating gastric cancer: a network pharmacology-based study.

Gastric cancer (GC) is a prevalent malignancy worldwide. Pulsatilla decoction (PD), a traditional Chinese medicine formula, can treat inflammatory bowel disease and cancers. In this study, we explored the bioactive components, potential targets, and molecular mechanisms of PD in the treatment of GC. We conducted a thorough search of online databases to gather gene data, active components, and potential target genes associated with the development of GC. Subsequently, we conducted bioinformatics analysis utilizing protein-protein interaction (PPI), network construction, and Kyoto Encyclopedia of Genes and Genomes (KEGG) to identify potential anticancer components and therapeutic targets of PD. Finally, the efficacy of PD in treating GC was further validated through in vitro experiments. Network pharmacological analysis identified 346 compounds and 180 potential target genes associated with the impact of PD on GC. The inhibitory effect of PD on GC may be mediated through modulation of key targets such as PI3K, AKT, NF-κB, FOS, NFKBIA, and others. KEGG analysis showed that PD mainly exerted its effect on GC through the PI3K-AKT, IL-17, and TNF signaling pathways. Cell viability and cell cycle experiments showed that PD could significantly inhibit proliferation and kill GC cells. Moreover, PD primarily induces apoptosis in GC cells. Western blotting analysis confirmed that the PI3K-AKT, IL-17, and TNF signaling pathways are the main mechanisms by which PD exerts its cytotoxic effects on GC cells. We have validated the molecular mechanism and potential therapeutic targets of PD in treating GC through network pharmacological analysis, thereby demonstrating its anticancer efficacy against GC.

Phosphoinositide and redox dysregulation by the anticancer methylthioadenosine phosphorylase transition state inhibitor

Methylthio-DADMe-immucillin-A (MTDIA) is an 86 picomolar inhibitor of 5′-methylthioadenosine phosphorylase (MTAP) with potent and specific anti-cancer efficacy. MTAP salvages S-adenosylmethionine (SAM) from 5′-methylthioadenosine (MTA), a toxic metabolite produced during polyamine biosynthesis. Changes in MTAP expression are implicated in cancer growth and development, making MTAP an appealing target for anti-cancer therapeutics. Since SAM is involved in lipid metabolism, we hypothesised that MTDIA alters the lipidomes of MTDIA-treated cells. To identify these effects, we analysed the lipid profiles of MTDIA-treated Saccharomyces cerevisiae using ultra-high resolution accurate mass spectrometry (UHRAMS). MTAP inhibition by MTDIA, and knockout of the Meu1 gene that encodes for MTAP in yeast, caused global lipidomic changes and differential abundance of lipids involved in cell signaling. The phosphoinositide kinase/phosphatase signaling network was specifically impaired upon MTDIA treatment, and was independently validated and further characterised via altered localization of proteins integral to this network. Functional consequences of dysregulated lipid metabolism included a decrease in reactive oxygen species (ROS) levels induced by MTDIA that was contemporaneous with changes in immunological response factors (nitric oxide, tumour necrosis factor-alpha and interleukin-10) in mammalian cells. These results indicate that lipid homeostasis alterations and concomitant downstream effects may be associated with MTDIA mechanistic efficacy.

Synthesis, modeling, and biological evaluation of anti-tubulin indole-substituted furanones

Due to the central role of tubulin in various cellular functions, it is a validated target for anti-cancer therapeutics. However, many of the current tubulin inhibitors are derived from complex natural products and suffer from multidrug resistance, low solubility, toxicity issues, and/or the lack of multi-cancer efficacy. As such, there is a continued need for the discovery and development of new anti-tubulin drugs to enter the pipeline. Herein we report on a group of indole-substituted furanones that were prepared and tested for anti-cancer activity. Molecular docking studies showed positive correlations between favorable binding in the colchicine binding site (CBS) of tubulin and anti-proliferative activity, and the most potent compound was found to inhibit tubulin polymerization. These compounds represent a promising new structural motif in the search for small heterocyclic CBS cancer inhibitors.

Design, synthesis, molecular dynamics simulation, MM/GBSA studies and kinesin spindle protein inhibitory evaluation of some 4-aminoquinoline hybrids

The discovery of novel chemotherapeutic agents is always challenging for researchers in industry and academia. Among the recent promising anticancer therapeutic targets, an important modulatory factor in mitosis is the expression of the kinesin family motor protein (Eg5). In terms of chemotherapy treatment, mitosis has gained significant attention due to its role as one of the biological processes that can be intervened in it. This study was undertaken to design, synthesise and evaluation of 4-aminoquinoline hybrid compounds as potential Eg5 inhibitors. Based on data collected from Malachite green and steady state ATPase assays, it has been determined that compounds such as 6c, 6d, 6g, and 6h are sensitive to Eg5 inhibition. In special mention, compounds 4 and 6c showed promising inhibitory activity in Malachite green assay with IC50 values of 2.32 ± 0.23 µM and 1.97 ± 0.23 µM respectively. Compound 4 showed favourable inhibitory potential Steady state ATPase Assay with IC50 value of 5.39 ± 1.39 µM. We performed molecular docking, MM/GBSA calculations, and molecular dynamic simulations to evaluate the interactions between ligands and the binding site of the kinesin spindle protein to evaluate the functional consequences of these interactions. As a result of these findings, it can be concluded that these 4-amioquinoline Schiff's base hybrids may prove to be promising candidates for development as novel inhibitors of Eg5. Further in-vivo research in this area is required.

The c-Src/LIST Positive Feedback Loop Sustains Tumor Progression and Chemoresistance.

Chemotherapy resistance and treatment failure hinder clinical cancer treatment. Src, the first mammalian proto-oncogene to be discovered, is a valuable anti-cancer therapeutic target. Although several c-Src inhibitors have reached the clinical stage, drug resistance remains a challenge during treatment. Herein, a positive feedback loop between a previously uncharacterized long non-coding RNA (lncRNA), which the authors renamed lncRNA-inducing c-Src tumor-promoting function (LIST), and c-Src is uncovered. LIST directly binds to and regulates the Y530 phosphorylation activity of c-Src. As a c-Src agonist, LIST promotes tumor chemoresistance and progression in vitro and in vivo in multiple cancer types. c-Src can positively regulate LIST transcription by activating the NF-κB signaling pathway and then recruiting the P65 transcription factor to the LIST promoter. Interestingly, the LIST/c-Src interaction is associated with evolutionary new variations of c-Src. It is proposed that the human-specific LIST/c-Src axis renders an extra layer of control over c-Src activity. Additionally, the LIST/c-Src axis is of high physiological relevance in cancer and may be a valuable prognostic biomarker and potential therapeutic target.

A hidden translatome in tumors-the coding lncRNAs.

Long noncoding RNAs (lncRNAs) have been extensively identified in eukaryotic genomes and have been shown to play critical roles in the development of multiple cancers. Through the application and development of ribosome analysis and sequencing technologies, advanced studies have discovered the translation of lncRNAs. Although lncRNAs were originally defined as noncoding RNAs, many lncRNAs actually contain small open reading frames that are translated into peptides. This opens a broad area for the functional investigation of lncRNAs. Here, we introduce prospective methods and databases for screening lncRNAs with functional polypeptides. We also summarize the specific lncRNA-encoded proteins and their molecular mechanisms that promote or inhibit cancerous. Importantly, the role of lncRNA-encoded peptides/proteins holds promise in cancer research, but some potential challenges remain unresolved. This review includes reports on lncRNA-encoded peptides or proteins in cancer, aiming to provide theoretical basis and related references to facilitate the discovery of more functional peptides encoded by lncRNA, and to further develop new anti-cancer therapeutic targets as well as clinical biomarkers of diagnosis and prognosis.

Abstract 2508: Clinical significance of PARP7 (TIPARP) gene copy number alterations in human non-small cell and head & neck carcinomas

Abstract Introduction: PARP7, encoded by the TIPARP gene, is a monoART involved in cellular stress responses and with immunomodulatory functions in cancer. The PARP7 gene is amplified in a subset of squamous cell carcinomas and ongoing clinical studies are assessing its role as anti-cancer therapeutic target (NCT04053673, NCT05127590) Here, we analyzed the frequency of PARP7 copy number alterations and its association with tumor immune microenvironment (TIME) features and outcomes in non-small cell lung cancer (NSCLC) and head & neck squamous-cell carcinoma (HNSCC) cohorts. Methods: The PARP7 gene copy number and amplification was analyzed using a dual probe fluorescence in situ hybridization (FISH) assay in two retrospective cohorts of NSCLC (Cohort #1, n=124) and HNSCC (Cohort #2, n=83) represented in tissue microarray format. In a subset of cases, the PARP7 copy number was also studied using whole exome DNA sequencing. The TIME was assessed on consecutive tumor sections using a multiplexed quantitative immunofluorescence panel including the markers DAPI, cytokeratin, CD4, CD8 and PD-L1 coupled to computational pathology analysis. The association between the markers, with clinicopathologic variables and survival was studied. Results: Increased PARP7 copy number (>2 copies/cell) was identified in 55% of NSCLCs (85% of them of squamous-cell histology) and 76% of HNSCCs. A high copy number (>3 copies/cell) was identified in 22% cases from both tumor type cohorts. After adjustment of the PARP7 gene copy number by the chromosome 3 centromeric probe (CEN3) signal, PARP7 amplification (>1.5 PARP7/CEN3 signal) was detected in 22% of NSCLC cases and 34% of HNSCC. A higher number of cases with PARP7 copy number gains were identified using FISH than with whole exome DNA sequencing. No significant associations between the PARP7 gains/losses and major clinicopathologic variables were found. However, higher PARP7 copy number was associated with reduced CD8+ or CD4+ tumor infiltrating lymphocytes (TILs) and a numerically lower tumor PD-L1 protein levels in HNSCC. Elevated PARP7 copy number was associated with shorter overall survival in both studied tumor types. Conclusion: Elevated PARP7 gene copy number identifies a subset of lung and head & neck squamous-cell carcinomas with unfavorable TIME features and adverse prognosis. Detection of PARP7 gene abnormalities using FISH in tumor biopsy samples is sensitive and has potential as a predictive biomarker. Citation Format: Viviana A. Ahumada, Kristen McEachern, Kristy Kuplast-Barr, Kurt Alex Schalper. Clinical significance of PARP7 (TIPARP) gene copy number alterations in human non-small cell and head & neck carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2508.