Biology subjects

Cho, W. C.

Publications and source records attributed to Cho, W. C..

3 recordsLinked to original sources

bioRxiv2026

Noncanonical Circular RNAs and Potential Functions

Circular RNAs (circRNAs) are ubiquitous in eukaryotes; dysregulated circRNA expression is linked to diseases, including lung cancer. In contrast to canonical circRNAs arising from exon-intron boundaries, noncanonical circRNAs originating within exonic, intronic, and intergenic regions have typically been dismissed as transcriptional noise or technical artifacts. To explore circRNA diversity and appreciate their functions, we developed an algorithm to identify both canonical and noncanonical circRNAs without relying on genome annotation, enabling the identification of circRNAs of all types and in newly sequenced or poorly annotated species. Results from lung cancer cells revealed that noncanonical circRNAs constituted over two-thirds of the circRNA population and were expressed more abundantly than canonical circRNAs, and genes with fewer and shorter exons were hotspots for noncanonical circRNA and circRNA isoform production. Further analyses showed that many noncanonical circRNAs were indeed endogenous circRNAs transcribed within cells rather than experimental artifacts, were potentially translated into proteins or peptides, and were conserved across species. Moreover, we validated 65 noncanonical circRNAs in NCI-H23 cells using multiple bioassays and demonstrated that both exonic and intergenic noncanonical circRNAs influenced cell viability. CircRNA profiles in tumor and tumor-adjacent tissues of lung cancer patients revealed tissue-specific expression and differentially expressed canonical and noncanonical circRNAs from cognate genes involved in cancer-related pathways, indicating their potential clinical relevance. This study confirmed the authenticity of noncanonical circRNAs and provided the first experimental evidence that noncanonical circRNAs influence cancer cell phenotypes. These findings broaden our understanding of circRNA biology, highlighting their widespread genomic distribution, diverse functions, and potential clinical relevance.

molecular biology↗

bioRxiv2026

Functional and sensitivity profiling of theKITMutation Landscape in Melanoma

Melanoma in Asia presents a unique epidemiological profile, with a higher prevalence of acral and mucosal subtypes compared to Western populations. While KIT mutations are found in up to 15% of Asian melanoma cases, clinical outcomes with KIT inhibitors have been modest due to heterogeneous mutation profiles and a lack of specific patient selection criteria. This study characterizes the landscape of KIT mutations in melanoma using the GENIE database, identifying 86 recurrent hotspots, many of which are variants of unknown significance (VUS). We validated drug sensitivities for key mutations using in vitro and in vivo models. Our results indicate that while the L576P mutation is highly sensitive to multiple inhibitors, the N822K mutation shows resistance to imatinib but responds to sunitinib, nilotinib, and nintedanib. These findings highlight the necessity of genotype-guided therapeutic strategies and provide a rationale for future clinical trials combining broad-spectrum KIT inhibitors with immune checkpoint inhibitors. Translational SignificanceMelanoma subtypes prevalent in Asia, specifically acral and mucosal melanoma, frequently harbor KIT mutations but show poor response rates (23-26%) to the standard-of-care inhibitor, imatinib. This study challenges the current clinical practice of treating all KIT-mutated melanomas uniformly. We demonstrate that specific recurrent mutations, such as N822K, are intrinsically resistant to imatinib but highly sensitive to broad-spectrum inhibitors like sunitinib and nintedanib. By establishing a comprehensive "lookup table" of drug sensitivities for both common and previously uncharacterized KIT variants, this work provides the evidence base required to transition from a "one-size-fits-all" approach to a genotype-guided precision medicine strategy. Furthermore, validating these targets informs the design of next-generation clinical trials, particularly those combining optimal KIT inhibitors with immune checkpoint blockade to improve survival in currently underserved patient populations.

cancer biology↗

bioRxiv2026

Mutation-Resolved Drug Sensitivity Atlas Reveals Broad RAS(ON) Inhibitor Vulnerabilities and a STAT3 Co-Dependency in NRAS-Mutant Melanoma

NRAS-mutated melanoma remains a major unmet clinical need, with no approved targeted therapy and rapid progression on standard treatment. Tri-complex RAS(ON) inhibitors such as daraxonrasib (RMC-6236) and RMC-7977 have shown early clinical activity, but the mutation-specific sensitivity landscape and adaptive resistance programs in melanoma remain undefined. To address this, we generated an isogenic 3D melanoma platform and performed a saturation mutagenesis screen across 95 NRAS missense variants (>99% of clinically recurrent variants), profiling oncogenic fitness and responses to six RAS-targeting agents in spheroids and xenografts. RMC-6236 and RMC-7977 showed the broadest activity and stratified recurrent NRAS mutants into hypersensitive (G12 variants and Q61R/K/L; [~]95% of cases), moderately sensitive (G13D/R/V; [~]4%), and resistant (G60E and Q61P; [~]1%) classes. Structural analyses supported distinct mechanisms underlying reduced susceptibility in a restricted subset of variants. In sensitive genotypes, RAS(ON) inhibition elicited an adaptive cytokine- and RTK-associated survival program converging on STAT3. Co-inhibition of STAT3 enhanced apoptosis, suppressed MYC, and induced tumor regression in NRAS-mutant melanoma models. Together, these findings define a mutation-resolved therapeutic landscape for NRAS-mutant melanoma and identify adaptive STAT3 signaling as a rational target for combination therapy. Statement of Translational SignificanceNRAS-mutated melanoma lacks effective targeted treatments, and clinical responses to immunotherapy are suboptimal. This study presents the first comprehensive drug sensitivity map across 95 NRAS mutations in melanoma, identifying the pan-RAS(ON) inhibitors RMC-6236 and RMC-7977 as broadly effective agents. Multiple mutants with reduced susceptibility are identified, providing mutation-informed guidance for patient selection and clinical trial stratification. Mechanistic analyses reveal that RTK/cytokine-driven STAT3 activation functions as a key survival pathway under RAS(ON) blockade, and its inhibition markedly enhances the efficacy of pan-RAS(ON) inhibitors. These findings support mutation-guided use of RAS(ON) inhibition and highlight STAT3 co-targeting as a rational strategy to strengthen and prolong therapeutic responses in NRAS-mutated melanoma. Highlights- A functional and therapeutic atlas defines 95 recurrent and nonrecurrent NRAS missense variants in melanoma - RMC-6236 and RMC-7977 show broad but genotype-selective activity across major NRAS mutations - A restricted subset of recurrent NRAS mutants shows reduced susceptibility to RAS(ON) inhibition - RAS(ON) inhibition induces an adaptive STAT3 survival program that is therapeutically targetable

cancer biology↗