Cuyler Luck

All Publications

• Modeling of Capicua Family Fusion Oncoprotein-Driven Cancers Reveals Gene-Specific Functionality MOLECULAR CANCER RESEARCH Luck, C., Luo, Y., Vasileva, E., Jacobs, K. A., Riad, J., Macaraig, C. D., Ponce, R. M., Amatruda, J. F., Okimoto, R. A. 2026; 24 (5): 337-355

  Abstract

  Clinical divergence between patients harboring Capicua (CIC) rearrangements is frequently observed. For example, the prototypical CIC::DUX4 fusion associates with soft-tissue tumors whereas CIC::NUTM1 fusions typically localize to the central nervous system (brain/spinal cord). The basis for these differences is poorly understood because of a lack of molecular tools. To address this need, we generated patient-informed, synthetic coding sequences for CIC::NUTM1, CIC::LEUTX, and ATXN1::DUX4 and validated them in structure-function studies and in genetic zebrafish models. We found that CIC::NUTM1 drives a transcriptional program distinct from that of CIC::DUX4 because of a C-terminal NUTM1 functional domain, CIC::LEUTX weakly activates CIC target genes through LEUTX transactivation sequences, and ATXN1::DUX4 upregulates CIC target genes via the ATXN1 AXH domain. Our findings indicate that the CIC fusion binding partner may alter overall fusion oncoprotein activity.These first-generation synthetic tools illuminate partner gene-specific mechanistic biology while providing an unprecedented resource to study CIC-family fusions beyond CIC::DUX4 and allow for the dissection of this rare subgroup of cancers.

  View details for DOI 10.1158/1541-7786.MCR-25-0624

  View details for Web of Science ID 001755722400010

  View details for PubMedID 41575738

  View details for PubMedCentralID PMC12930430

• The CIC::DUX4 oncoprotein maintains DNA integrity through direct regulation of the catalytic subunit of DNA polymerase epsilon (POLE) ONCOGENE Kosibaty, Z., Luck, C., Okimoto, R. A. 2025; 44 (38): 3598-3608

  Abstract

  Transcription factor (TF) fusion oncoproteins represent cancer-specific alterations that arise from chromosomal rearrangements. Through target gene recognition, TF fusions can disseminate transcriptional responses that collectively work to drive tumorigenesis. Thus, identifying the molecular targets that operate as a disease-driving network can potentially uncover key actionable dependencies. We have taken this strategy to dissect the underlying biological mechanism by which CIC::DUX4, a fusion oncoprotein associated with dismal outcomes, drives sarcomagenesis. We and others have defined a CIC::DUX4 fusion-mediated network that dysregulates cell-cycle and DNA replication checkpoints. Specifically, CIC::DUX4-mediated CCNE1 upregulation compromises the G1/S transition, leading to high DNA replication stress and conferring a dependence on the G2/M checkpoint kinase, WEE1. WEE1 provides a molecular brake to enable effective DNA repair prior to mitotic entry. Importantly, the mechanism by which CIC::DUX4 regulates DNA repair remains unknown. Here we show that the catalytic subunit of DNA polymerase epsilon (POLE) is essential for DNA integrity and cellular division in CIC::DUX4 sarcoma. Mechanistically, POLE loss increases DNA damage and induces p21-mediated cellular senescence to limit CIC::DUX4 tumor growth in vitro and tumor formation in vivo. Collectively, we credential POLE as a CIC::DUX4 target and further characterize a functional network through which CIC::DUX4 operates to drive tumor progression and survival.

  View details for DOI 10.1038/s41388-025-03507-9

  View details for Web of Science ID 001543255200001

  View details for PubMedID 40760094

  View details for PubMedCentralID PMC12436161

• First Generation Tools for the Modeling of Capicua (CIC) - Family Fusion Oncoprotein-Driven Cancers. bioRxiv : the preprint server for biology Luck, C., Jacobs, K. A., Riad, J., Macaraig, C. D., Ponce, R. K., Okimoto, R. A. 2025

  Abstract

  Clinical divergence between patients harboring CIC-rearrangements is frequently observed. For example, the prototypical CIC::DUX4 fusion associates with soft tissue tumors while CIC::NUTM1 fusions typically localize to the CNS (brain/spinal cord). The basis for these differences is poorly understood due to a lack of molecular tools. To address this need, we generated patient-informed, synthetic coding sequences for CIC::NUTM1, CIC::LEUTX, and ATXN1::DUX4 and validated them in structure-function studies. We found that CIC::NUTM1 drives a transcriptional program distinct from that of CIC::DUX4 due to a C-terminal NUTM1 functional domain, CIC::LEUTX weakly activates CIC target genes through LEUTX transactivation sequences, and ATXN1::DUX4 upregulates CIC target genes via the ATXN1 AXH domain. Our findings indicate that the CIC fusion binding partner may alter overall fusion oncoprotein activity. Thus, these first generation synthetic tools provide an unprecedented resource to study CIC-family fusions beyond CIC::DUX4 and allow for the dissection of this rare subgroup of cancers.

  View details for DOI 10.1101/2025.05.13.653825

  View details for PubMedID 40463157

• The <i>Capicua</i> C1 Domain Is Required for Full Activity of the CIC::DUX4 Fusion Oncoprotein CANCER RESEARCH COMMUNICATIONS Luck, C., Jacobs, K. A., Okimoto, R. A. 2024; 4 (12): 3099-3113

  Abstract

  Rearrangements between genes can yield neomorphic fusions that drive oncogenesis. Fusion oncogenes are made up of fractional segments of the partner genes that comprise them, with each partner potentially contributing some of its own function to the nascent fusion oncoprotein. Clinically, fusion oncoproteins driving one diagnostic entity are typically clustered into a single molecular subset and are often treated a similar fashion. However, knowledge of where specific fusion breakpoints occur in partner genes, and the resulting retention of functional domains in the fusion, is an important determinant of fusion oncoprotein activity and may differ between patients. This study investigates these phenomena through the example of capicua (CIC)::double homeobox 4 (DUX4), a fusion between transcriptional repressor CIC and DUX4 genes, which drives an aggressive subset of undifferentiated round cell sarcoma. Using a harmonized dataset of more than 100 patient fusion breakpoints from the literature, we show that most bona fide CIC::DUX4 fusions retain the C1 domain, which is known to contribute to DNA binding by wild-type CIC. Mechanistically, deletion or mutation of the C1 domain reduces, but does not eliminate, the activation of CIC target genes by CIC::DUX4. We also find that expression of C1-deleted CIC::DUX4 is capable of exerting intermediate transformation-related phenotypes compared with those imparted by full-length CIC::DUX4 but was not sufficient for tumorigenesis in a subcutaneous mouse model. In summary, our results suggest a supercharging role for the C1 domain in the activity of CIC::DUX4.We show in mammalian settings that the capicua C1 functional domain is a supercharger for CIC::DUX4, a poorly studied fusion oncoprotein which drives a rare sarcoma with dismal outcomes.

  View details for DOI 10.1158/2767-9764.CRC-24-0348

  View details for Web of Science ID 001372175700002

  View details for PubMedID 39530749

  View details for PubMedCentralID PMC11626509

• TheCapicuaC1 Domain is Required for Full Activity of the CIC::DUX4 Fusion Oncoprotein. bioRxiv : the preprint server for biology Luck, C., Jacobs, K. A., Okimoto, R. A. 2024

  Abstract

  Rearrangements between genes can yield neomorphic fusions that drive oncogenesis. Fusion oncogenes are made up of fractional segments of the partner genes that comprise them, with each partner potentially contributing some of its own function to the nascent fusion oncoprotein. Clinically, fusion oncoproteins driving one diagnostic entity are typically clustered into a single molecular subset and are often treated a similar fashion. However, knowledge of where specific fusion breakpoints occur in partner genes, and the resulting retention of functional domains in the fusion, is an important determinant of fusion oncoprotein activity and may differ between patients. This study investigates this phenomena through the example of CIC::DUX4, a fusion between the transcriptional repressor capicua (CIC) and the double homeobox 4 gene (DUX4), which drives an aggressive subset of undifferentiated round cell sarcoma. Using a harmonized dataset of over 100 patient fusion breakpoints from the literature, we show that most bona fide CIC::DUX4 fusions retain the C1 domain, which is known to contribute to DNA binding by wild type CIC. Mechanistically, deletion or mutation of the C1 domain reduces, but does not eliminate, activation of CIC target genes by CIC::DUX4. We also find that expression of C1-deleted CIC::DUX4 is capable of exerting intermediate transformation-related phenotypes compared with those imparted by full-length CIC::DUX4, but was not sufficient for tumorigenesis in a subcutaneous mouse model. In summary, our results suggest a supercharging role for the C1 domain in the activity of CIC::DUX4.

  View details for DOI 10.1101/2024.06.06.597815

  View details for PubMedID 38895482

• Molecular and therapeutic advancements in Capicua (<i>CIC</i>)-rearranged sarcoma FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY Ponce, R. M., Luck, C., Okimoto, R. A. 2024; 12: 1416697

  Abstract

  Capicua (CIC)-rearranged sarcomas are an aggressive subset of undifferentiated round cell sarcomas. CIC::DUX4, the proto-typical CIC fusion oncoprotein is associated with rapid clinical progression and chemotherapy resistance leading to poor clinical outcomes. Recent studies have identified additional CIC fusions (CIC::NUTM1, CIC::FOXO4, and CIC::LEUTX) that largely retain CIC-binding specificity but leverage C-terminal binding partners (NUTM1, FOXO4, and LEUTX) to potentially activate transcriptional programs that drive oncogenesis. Moreover, the recent development of preclinical models to study CIC::DUX4 sarcoma have advanced our understanding of the underlying biological mechanisms and uncovered key dependencies that can be translated into rational therapies. In this review, we will highlight these recent advancements in CIC-rearranged sarcoma biology with a vision for clinical translation to improve patient outcomes.

  View details for DOI 10.3389/fcell.2024.1416697

  View details for Web of Science ID 001247084900001

  View details for PubMedID 38882060

  View details for PubMedCentralID PMC11176417

• Allosteric SHP2 inhibition increases apoptotic dependency on BCL2 and synergizes with venetoclax in<i> FLT3-</i> and<i> KIT</i>-mutant AML CELL REPORTS MEDICINE Popescu, B., Stahlhut, C., Tarver, T. C., Wishner, S., Lee, B. J., Peretz, C. A. C., Luck, C., Phojanakong, P., Serrano, J., Hongo, H., Rivera, J. M., Xirenayi, S., Chukinas, J. A., Steri, V., Tasian, S. K., Stieglitz, E., Smith, C. C. 2023; 4 (11): 101290

  Abstract

  Mutations in the receptor tyrosine kinases (RTKs) FLT3 and KIT are frequent and associated with poor outcomes in acute myeloid leukemia (AML). Although selective FLT3 inhibitors (FLT3i) are clinically effective, remissions are short-lived due to secondary resistance characterized by acquired mutations constitutively activating the RAS/MAPK pathway. Hereby, we report the pre-clinical efficacy of co-targeting SHP2, a critical node in MAPK signaling, and BCL2 in RTK-driven AML. The allosteric SHP2 inhibitor RMC-4550 suppresses proliferation of AML cell lines with FLT3 and KIT mutations, including cell lines with acquired resistance to FLT3i. We demonstrate that pharmacologic SHP2 inhibition unveils an Achilles' heel of RTK-driven AML, increasing apoptotic dependency on BCL2 via MAPK-dependent mechanisms, including upregulation of BMF and downregulation of MCL1. Consequently, RMC-4550 and venetoclax are synergistically lethal in AML cell lines and in clinically relevant xenograft models. Our results provide mechanistic rationale and pre-clinical evidence for co-targeting SHP2 and BCL2 in RTK-driven AML.

  View details for DOI 10.1016/j.xcrm.2023.101290

  View details for Web of Science ID 001123403800001

  View details for PubMedID 37992684

  View details for PubMedCentralID PMC10694768

• Osteosarcoma PDX-Derived Cell Line Models for Preclinical Drug Evaluation Demonstrate Metastasis Inhibition by Dinaciclib through a Genome-Targeted Approach. Clinical cancer research : an official journal of the American Association for Cancer Research Schott, C. R., Koehne, A. L., Sayles, L. C., Young, E. P., Luck, C., Yu, K., Lee, A. G., Breese, M. R., Leung, S. G., Xu, H., Shah, A. T., Liu, H. Y., Spillinger, A., Behroozfard, I. H., Marini, K. D., Dinh, P. T., Pons Ventura, M. V., Vanderboon, E. N., Hazard, F. K., Cho, S. J., Avedian, R. S., Mohler, D. G., Zimel, M., Wustrack, R., Curtis, C., Sirota, M., Sweet-Cordero, E. A. 2023: OF1-OF16

  Abstract

  Models to study metastatic disease in rare cancers are needed to advance preclinical therapeutics and to gain insight into disease biology. Osteosarcoma is a rare cancer with a complex genomic landscape in which outcomes for patients with metastatic disease are poor. As osteosarcoma genomes are highly heterogeneous, multiple models are needed to fully elucidate key aspects of disease biology and to recapitulate clinically relevant phenotypes.Matched patient samples, patient-derived xenografts (PDX), and PDX-derived cell lines were comprehensively evaluated using whole-genome sequencing and RNA sequencing. The in vivo metastatic phenotype of the PDX-derived cell lines was characterized in both an intravenous and an orthotopic murine model. As a proof-of-concept study, we tested the preclinical effectiveness of a cyclin-dependent kinase inhibitor on the growth of metastatic tumors in an orthotopic amputation model.PDXs and PDX-derived cell lines largely maintained the expression profiles of the patient from which they were derived despite the emergence of whole-genome duplication in a subset of cell lines. The cell lines were heterogeneous in their metastatic capacity, and heterogeneous tissue tropism was observed in both intravenous and orthotopic models. Single-agent dinaciclib was effective at dramatically reducing the metastatic burden.The variation in metastasis predilection sites between osteosarcoma PDX-derived cell lines demonstrates their ability to recapitulate the spectrum of the disease observed in patients. We describe here a panel of new osteosarcoma PDX-derived cell lines that we believe will be of wide use to the osteosarcoma research community.

  View details for DOI 10.1158/1078-0432.CCR-23-0873

  View details for PubMedID 37703185

• Capicua suppresses<i> YAP1</i> to limit tumorigenesis and maintain drug sensitivity in human cancer CELL REPORTS Won Kim, J., Luck, C., Wu, W., Ponce, R., Lin, Y., Gupta, N., Okimoto, R. A. 2022; 41 (1): 111443

  Abstract

  Inactivation of Capicua (CIC) or upregulation of yes-associated protein 1, YAP1, leads to broad RAS-RAF-MEK-ERK inhibitor resistance and tumor progression in multiple human cancers. Despite these shared malignant phenotypes, it remains unclear whether CIC and YAP1 are mechanistically linked. Here, we show that the ERK-regulated transcription factor CIC can directly repress YAP1 expression through non-consensus GGAAGGAA DNA-binding motifs in a proximal YAP1 regulatory element. Through binding at GGAA repeats, CIC regulates YAP1 transcriptional output in both normal and human cancer cells. Silencing YAP1 in CIC-deficient cells restores MAPK inhibitor sensitivity and suppresses tumor growth. Thus, we uncover a molecular link between the MAPK-ERK effector CIC and YAP1 in human cells and established YAP inhibition as a strategy to target CIC-deficient cancers.

  View details for DOI 10.1016/j.celrep.2022.111443

  View details for Web of Science ID 000869543500004

  View details for PubMedID 36198276

  View details for PubMedCentralID PMC9674208

• Atypical Molecular Basis for Drug Resistance to Mitochondrial Function Inhibitors in <i>Plasmodium falciparum</i> ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Painter, H. J., Morrisey, J. M., Mather, M. W., Orchard, L. M., Luck, C., Smilkstein, M. J., Riscoe, M. K., Vaidya, A. B., Llinas, M. 2021; 65 (3)

  Abstract

  The continued emergence of drug-resistant Plasmodium falciparum parasites hinders global attempts to eradicate malaria, emphasizing the need to identify new antimalarial drugs. Attractive targets for chemotherapeutic intervention are the cytochrome (cyt) bc1 complex, which is an essential component of the mitochondrial electron transport chain (mtETC) required for ubiquinone recycling and mitochondrially localized dihydroorotate dehydrogenase (DHODH) critical for de novo pyrimidine synthesis. Despite the essentiality of this complex, resistance to a novel acridone class of compounds targeting cyt bc1 was readily attained, resulting in a parasite strain (SB1-A6) that was panresistant to both mtETC and DHODH inhibitors. Here, we describe the molecular mechanism behind the resistance of the SB1-A6 parasite line, which lacks the common cyt bc1 point mutations characteristic of resistance to mtETC inhibitors. Using Illumina whole-genome sequencing, we have identified both a copy number variation (∼2×) and a single-nucleotide polymorphism (C276F) associated with pfdhodh in SB1-A6. We have characterized the role of both genetic lesions by mimicking the copy number variation via episomal expression of pfdhodh and introducing the identified single nucleotide polymorphism (SNP) using CRISPR-Cas9 and assessed their contributions to drug resistance. Although both of these genetic polymorphisms have been previously identified as contributing to both DSM-1 and atovaquone resistance, SB1-A6 represents a unique genotype in which both alterations are present in a single line, suggesting that the combination contributes to the panresistant phenotype. This novel mechanism of resistance to mtETC inhibition has critical implications for the development of future drugs targeting the bc1 complex or de novo pyrimidine synthesis that could help guide future antimalarial combination therapies and reduce the rapid development of drug resistance in the field.

  View details for DOI 10.1128/AAC.02143-20

  View details for Web of Science ID 000619864100043

  View details for PubMedID 33361312

  View details for PubMedCentralID PMC8092505