Oestrogen receptor (ER) activation leads to the formation of DNA double strand breaks (DSB), promoting genomic instability and tumour heterogeneity. The single-stranded DNA cytosine deaminase APOBEC3B (A3B) serves as a co-activator of ER and is implicated in inducing DSBs at transcriptional enhancers regulated by ER. Using whole-genome sequencing in an engineered cell model lacking base excision repair (BER) function, we demonstrate that A3B preferentially targets transcriptionally active regulatory regions in an R-loop-dependent manner. Strand-specific DNA:RNA immunoprecipitation sequencing (ssDRIP-seq) and ssDNA-associated protein immunoprecipitation sequencing (SPI-seq) confirm that A3B binds to and deaminates ssDNA within R-loops, a process facilitated by ER transactivation. Furthermore, BER-mediated processing of A3B-induced uracil bases contributes to the formation of R-loop-associated DSBs, which are essential for ER-regulated gene activation. These findings establish a role for A3B in R-loop homeostasis and transcriptional regulation, with implications for understanding ER-driven genomic instability and potential therapeutic targeting of A3B.

Despite recent therapeutic advances, advanced prostate cancer (PCa) remains lethal as tumors develop resistance to current treatments. Novel and more effective therapeutic strategies to induce cell death in these tumors are urgently needed. Our group recently reported that NXP800, a drug in clinical development, drives unfolded protein response (UPR) and targets AR and E2F, decreasing the growth of castration-resistant PCa (CRPC) models in vitro and in vivo. BH3 mimetics are small molecules that inhibit antiapoptotic BCL-2 family proteins, thereby promoting apoptosis, and have shown particular promise in hematological malignancies. However, their efficacy in CRPC has been limited, likely due to functional redundancies among antiapoptotic proteins such as MCL1, BCLXL, and BCL2. We investigated the potential of combining NXP800 with BH3 mimetics targeting MCL1 (S63845) or BCLXL (A-1331852) to drive cell death by inducing the intrinsic apoptosis pathway in CRPC models. Cell viability and caspase 3/7 activity were assessed by luminescence assays, while additional apoptosis markers were evaluated by western blot following treatment with NXP800, S63845, and A-1331852, as single agents or in combination. To identify key mediators of the synergistic effects, an siRNA screen targeting BH3-only proteins was performed in CRPC cells before treatment with the single agents or their combination. To assess the molecular consequences of NXP800 treatment in vivo, RNA-seq was performed on tumors from CRPC-bearing mice treated with NXP800 (35 mg/kg daily for 5 days), with particular focus on genes involved in the intrinsic apoptosis pathway. NXP800 synergized with MCL1 and BCLXL inhibitors in CRPC cells, inducing apoptosis as evidenced by caspase 3/7 activation and PARP cleavage. Co-silencing of the mitochondrial pore–forming proteins BAX and BAK, as well as treatment with the pan-caspase inhibitor Q-VD-OPh, prevented cell death induced by NXP800 in combination with BH3 mimetics, indicating that the effect is caspase-dependent and involves activation of the intrinsic apoptosis pathway. Blocking NXP800-induced eIF2α phosphorylation using ISRIB abolished the synergistic effect observed with BH3 mimetics. Thapsigargin, which induces the unfolded protein response via SERCA inhibition, recapitulated the synergy and triggered apoptosis in combination with BH3 mimetics. RNA-seq analysis of LNCaP95 xenograft tumors treated with NXP800 revealed induction of specific BH3-only proteins whose silencing (in vitro) prevented caspase 3/7 activation and abolished the synergistic cell death observed with NXP800 in combination with MCL1 or BCLXL inhibition. NXP800 sensitizes CRPC cells to BH3 mimetics by inducing UPR and dysregulating BH3-only proteins. These findings highlight the potential of combining UPR-inducing agents with BH3 mimetics as a therapeutic strategy in CRPC. Juan M. Jiménez-Vacas, Jonathan Welti, Denisa Bogdan, Ines Figueiredo, Bora Gurel, Wanting Zeng, Tomas Goldsmith, Souvik Das, Joe Taylor, Nicholas Waldron, Claudia Bertan, Suzanne Carreira, Wei Yuan, Paul Workman, Steven P. Balk, Johann de Bono, Adam Sharp. Induction of the unfolded protein response unveils a vulnerability of advanced prostate cancer cells to BH3 mimetics [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr B032.

Proteolysis TArgeting Chimeras (PROTACs) can be used to target both the catalytic and noncatalytic functions of a protein, which can be particularly beneficial for proteins with important scaffolding functions like Aurora A. However, instability, poor selectivity profiles, and the hook effect often limit the applicability of PROTACs as chemical probes. In this study, we report the development of CCT400028, a second-generation alisertib-derived Aurora A PROTAC. The hook effect was removed through rational optimization of the CRBN-targeting warhead to decrease affinity for cereblon, which, combined with improved stability to hydrolysis, expands the range of concentrations and duration at which maximal degradation can be achieved. Potent Aurora A degradation was shown in three pediatric tumor cell lines, as well as excellent selectivity and on-target mechanism of action. CCT400028 and a matched inactive control analogue fulfill the criteria for a degrader chemical probe for studying Aurora A degradation in vitro.

Human DHX8 is a spliceosomal DEAH-box RNA helicase involved in releasing mRNA from the spliceosome and crucial in ensuring splicing fidelity. DHX8 was identified as a promising therapeutic oncology target due to its role in regulating stress-adaptive gene expression, including HSF1-dependent transcription, while having broader transcriptional effects in cells under oncogenic stress. We report the discovery of novel RNA-competitive DHX8 inhibitors based on a 2-(phenethylthio)nicotinic acid scaffold, which were optimized using a structure-guided design approach, following a biophysical fragment screen. This yielded compound 53 with nanomolar biochemical potency, good in vitro PK, and activity in a cellular target engagement assay. Optimizing inhibitor binding between Arg647 and the nonconserved His693, coupled with extending into a pocket in the DHX8 Winged-Helix domain, was crucial for potency improvement. By binding in the Winged-Helix domain, these inhibitors restrict the helicase domain’s conformational plasticity, stabilizing a closed, inactive conformation while sterically blocking ssRNA translocation.

Advances in preclinical models that recapitulate chemorefractory and relapsed disease are needed to better predict the efficacy of an expanding and promising armamentarium of drug candidates being tested in early-phase pediatric clinical trials. Here, we used longitudinal magnetic resonance imaging to design an individualized, dose-escalating treatment regimen that induces evolution of neuroblastoma in the Th-MYCN genetically-engineered mouse model, concomitant with the acquisition of resistance to temozolomide, a standard chemotherapy used in treatment of refractory, relapsed neuroblastoma patients within European early-phase clinical trials. MRI longitudinally identified the development of intra-tumoral heterogeneity. Molecular profiling of expanding, treatment-refractory regions identified prominent up-regulation of the noradrenergic core regulatory signature and deregulation of the CDK2 pathway. Treatment with the CDK2/9 inhibitor fadraciclib led to significant response and an overall survival benefit in temozolomide-resistant Th-MYCN tumors and allografts generated from these resistant tumours. These findings demonstrate the utility of genetically-engineered mouse models as platforms to dissect the evolution of chemoresistance in neuroblastoma and they provide a mechanistic rationale to support the evaluation of fadraciclib in ongoing paediatric phase I studies of chemotherapy combined with temozolomide in relapsed, treatment refractory neuroblastoma patients.

For the 25th anniversary of Nature Reviews Cancer, we invited six researchers to reflect on the past 25 years of cancer research, highlighting the most transformative conceptual advances, as well as those that did not fulfil their initial promise or were fundamentally misunderstood. To mark the 25th anniversary of Nature Reviews Cancer, six researchers reflect on the conceptual advances that have reshaped cancer research — from somatic mosaicism, functional genomics and cancer stem cells to tumour metabolism, precision oncology and artificial intelligence — and consider which ideas transformed the field, which fell short of expectations, and what challenges remain.

Transcription factor heat shock factor 1 (HSF1) orchestrates the cellular stress response, promoting malignant transformation, unchecked proliferation, and stress-resilient survival of tumour cells. We set out to discover potentially druggable regulators of HSF1 activation and identified DEAH-box RNA helicase 8 (DHX8). We investigated the role of DHX8 in regulating HSF1 within the broader context of DHX8 function in cancer cells. DHX8 silencing induces intron retention in HSF1 transcripts, reducing HSF1 protein. Importantly, DHX8 loss significantly alters RNA processing of an HSF1-regulated cancer-associated gene signature linked to poor clinical outcomes, as well as additional oncogenic and stress-response pathways. DHX8 binds between the pre-messenger RNA (mRNA) lariat branch point and the 3' splice site, consistent with the predominance of intron-retained transcripts following DHX8 loss. We show that both the ATPase and RNA-binding activities of DHX8 are essential for its role in splicing, including processing of HSF1 mRNA. We also find that DHX8 silencing triggers apoptosis more effectively in human cancer cells than in non-tumorigenic cells. Our findings identify DHX8 as a critical regulator of stress-adaptive gene expression, highlighting its promise as a therapeutic target not only to disrupt HSF1-dependent transcriptional programs but also having broader effects in cancer cells under oncogenic stress.

Abstract Background: Heat Shock Factor 1 (HSF1) drives stress tolerance, oncogenic transformation, and survival in diverse human cancers. Although pharmacologic inhibition of HSF1 remains challenging, identifying druggable upstream regulators of HSF1 offers a promising alternative strategy to disrupt stress adaptation in tumours. Methods: A focused siRNA screen targeting 7,598 druggable genes was performed in human osteosarcoma cells to identify modulators of HSF1-activation. Transcriptomic, RNA immunoprecipitation (RIP), and enhanced CLIP (eCLIP) analyses were used to define the function and RNA-binding sites of the DEAH-box RNA helicase 8 (DHX8). Genetic rescue with wild-type versus ATPase- and RNA-binding-defective DHX8 mutants validated the mechanistic requirements for HSF1 mRNA processing. Functional assays (viability, cell cycle, apoptosis) assessed the effects of DHX8 depletion across tumorigenic and non-tumorigenic cell lines. Results: DHX8 was identified and validated as a potent regulator of the HSF1 stress response. DHX8 silencing led to the accumulation of intron-retained HSF1 transcripts, decreased HSF1 protein levels, and suppression of HSF1 target genes. Genome-wide RNA-seq revealed broad DHX8-dependent splicing changes, dominated by intron retention, affecting>1,300 mRNAs. eCLIP profiling identified DHX8 binding between the lariat branch site and 3′ splice junction, consistent with its role in late-stage mRNA splicing. Rescue experiments demonstrated that both ATPase and RNA-binding activities are essential for HSF1 mRNA maturation. Acute degradation of DHX8 using a dTAG system phenocopied siRNA knockdown, confirming on-target effects. Functionally, DHX8 depletion in tissue culture experiments was generally tolerated by non-tumorigenic lines, but induced G2/M arrest, apoptosis, and loss of viability in cancer cells. Conclusions: DHX8 is a key regulator of HSF1 mRNA processing and cancer-associated splicing programs. Loss of DHX8 disrupts the oncogenic stress response, suppresses heat shock gene induction, and preferentially kills tumour cells. These findings establish DHX8 as a potentially druggable node linking RNA splicing to HSF1-driven cancer-survival pathways, offering a new therapeutic entry point for targeting stress resilience in malignancy. Citation Format: Jennifer R. Tall, Robert Te Poele, Alexandra Vasile, Pradeep Ramagiri, Caitlin Davies, Marissa Powers, Toby Roe, Deivendran Sankaran, Konstantinos Mitsopoulos, Bissan Al-Lazikani, Robert L. Van Montfort, Emmanuel de Billy, Paul Workman, Paul A. Clarke, . Human DEAH-box RNA helicase 8 regulates HSF1-mediated stress response and cancer-associated pre-mRNA splicing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6005.

Supplementary figure 4: NXP800 decreases basal HSP72 protein levels and blocks HSP72 protein induction in response to HSP90 inhibition in PCa cell lines

Supplementary figure 8: NXP800 does not further impact AR transactivation or AR signaling in NXP800-resistant 22Rv1 PCa cell sub-lines.

NXP800 inhibits the growth of AR-dependent and AR-independent prostate cancer models with activation of the UPR and inhibition of key signaling pathways. A and B, PDX-O [CP50, CP89, CP129, and CP142 (A)], AR-positive (VCaP, LNCaP, LNCaP95, and 22Rv1), and AR-negative (PC3 and DU145) prostate cancer cell lines (B) were treated with vehicle (DMSO 0.1%) or various concentrations (5, 10, 50, 100, and 250 nmol/L) of NXP800 (active, red line), CCT365248 (inactive, blue line), and in the case of organoids, various concentrations (1 and 10 μmol/L) of enzalutamide (gray scale), and growth was determined after 5 days for cell lines and 7 days for organoids by CellTiter-Glo Cell Viability Assay as defined in “Materials and Methods.” Mean growth (compared with vehicle; defined as 1) with SD from a single experiment with three to six replicates is shown. *Abiraterone given in the castration-sensitive setting. ^CP89 and CP129 derived from two temporally separated mCRPC biopsies from the same patient. P values were calculated for NXP800 compared with CCT365248 for each concentration and for enzalutamide, compared with vehicle using the unpaired Student t test. P values ≤ 0.05 are shown (*). C–E, VCaP, LNCaP95, and 22Rv1 prostate cancer cells were treated with NXP800 (active, 100 or 250 nmol/L) or CCT365248 (inactive, 250 nmol/L) for 48 hours. RNA-seq was performed on each single experiment in triplicate (duplicate for 250 nmol/L NXP800 in LNCaP95). Analysis of RNA-seq with gene set enrichment analysis shows the enrichment and de-enrichment of Hallmark pathways in response to 100 and 250 nmol/L NXP800 (compared with 250 nmol/L CCT365248) in VCaP (C), LNCaP95 (D), and 22Rv1 (E) prostate cancer cells. NES and FDR are shown as volcano plots. Colored dots denote significantly (FDR 0.05) enriched (red dots) and de-enriched (blue dots) pathways with NXP800 (active compound) treatment. Table shows the NES associated with pathways wherein the FDR was ≤0.05 for 100 and/or 250 nmol/L (asterisk indicates those in which FDR was >0.05). F, VCaP (A), LNCaP95 (B), and 22Rv1 (C) prostate cancer cells were treated with NXP800 (active, 100 or 250 nmol/L) or CCT365248 (inactive, 250 nmol/L) for 48 hours. RNA-seq was performed on each single experiment in triplicate (duplicate for 250 nmol/L NXP800 in LNCaP95). Log2 fold expression level changes of “activating” E2F (E2F1–3) family members treated with NXP800 (active, 100 or 250 nmol/L) were compared with CCT365248 (inactive, 250 nmol/L). P values were calculated by DESeq2 using the Wald test. P values ≤ 0.05 are shown (*). G, VCaP, LNCaP95, and 22Rv1 prostate cancer cells were treated with 250 nmol/L CCT365248 (inactive) or 250 nmol/L NXP800 (active) for 24 hours. PERK, phospho-eIF2α, and ATF4 (PERK arm); ATF6 (ATF6 arm); IRE1 (IRE1 arm); E2F1 (E2F); and GAPDH (housekeeping) protein expression was determined by Western blot from one experiment performed in triplicate. H, Association between GO cellular response to heat gene expression signature and Hallmark E2F Targets in transcriptome cohorts of patients with PCF-SU2C and ICR-RMH. Pearson r and P values are shown.

Chemical probes are powerful small-molecule tools in fundamental and translational cancer research. They are highly versatile, complementing genetic technologies in the annotation of protein function, and invaluable in target validation and drug discovery. However, continued improvements are needed to enhance best practices in selection and use of chemical probes. We discuss progress over the last decade, highlight key issues, and indicate a path to generate a high-quality chemical probe for every human protein.

Supplementary figure 6: Inhibition of the unfolded protein response with ISRIB rescues NXP800-mediated suppression of AR signaling and PCa model growth

The Mediator complex is a regulator of gene expression, influencing chromatin structure and RNA polymerase II-mediated transcription. Its activity is controlled by a protein kinase module, which includes cyclin-dependent kinases 8 and 19, that phosphorylates RNA polymerase II and transcription factors to regulate gene expression. Using orthogonal approaches combining chemical and genetic tools, we demonstrated the selectivity of our small-molecule inhibitors derived from 3,4,5-trisubstituted pyridine and 3-methyl-1H-pyrazolo[3,4-b]pyridine chemical series in human colorectal cell culture and tumor xenograft models. The lack of activity of our inhibitors in CDK8/19 double knockout models, with respect to molecular, proliferative, and antitumor end points, revealed their specificity and dependence on these kinases. Using our chemical probes and knockout models, we explored Mediator kinase function in human colorectal cancer cells. Phospho-proteome profiling revealed substrates enriched with transcription and chromatin regulators, while promoter reporter experiments identified transcription factor binding sites, including TCF/LEF and AP1, regulated by Mediator kinases. Additionally, altered phosphorylation of several Mediator subunits suggests a mechanism for the rapid regulation of the Mediator complex. Overall, our results demonstrate that CDK8 and CDK19 play pivotal roles in regulating gene expression associated with oncogene activation and signaling pathways. Further studies are warranted to elucidate their broader cellular roles and regulatory mechanisms. The selective inhibitors validated in this study will provide valuable tools for such mechanistic investigations into Mediator kinase functions and their potential therapeutic exploitation.

Brachyury is a transcription factor that plays an essential role in tumour growth of the rare bone cancer chordoma and is implicated in other solid tumours. Brachyury is minimally expressed in healthy tissues, making it a potential therapeutic target. Unfortunately, as a ligandless transcription factor, brachyury has historically been considered undruggable. To investigate direct targeting of brachyury by small molecules, we determine the structure of human brachyury both alone and in complex with DNA. The structures provide insights into DNA binding and the context of the chordoma associated G177D variant. We use crystallographic fragment screening to identify hotspots on numerous pockets on the brachyury surface. Finally, we perform follow-up chemistry on fragment hits and describe the progression of a thiazole chemical series into binders with low µM potency. Thus we show that brachyury is ligandable and provide an example of how crystallographic fragment screening may be used to target protein classes that are difficult to address using other approaches.

GO cellular response to heat gene expression signature associates with AR signaling and poorer prognosis in men suffering from CRPC. A and G, Two independent (PCF-SU2C and ICR-RMH) transcriptome cohorts of patients with CRPC. Quantification of GO cellular response to heat gene expression signature in each transcriptome cohort of patients with CRPC in the PCF-SU2C (A) and ICR-RMH (G) CRPC cohorts. Biopsies (red dots) with GO cellular response to heat gene expression signature >80th percentile (dotted line) are shown. B and H, Kaplan–Meier curves for OS from CRPC biopsy by >80th percentile (red) or ≤80th percentile (gray) GO cellular response to heat gene expression signature in PCF-SU2C (B) and ICR-RMH (H) transcriptome cohorts. Median OS is shown. HR with 95% CI and P values for univariate Cox survival model are shown. C–F and I–L, Association between GO cellular response to heat gene expression signature and Hallmark Androgen Response, AR signature, Nelson Response to Androgen Up, and AR-V7 signature in transcriptome cohorts of patients with PCF-SU2C (C–F) and ICR-RMH (I–L). Pearson r and P values are shown.

Abstract Purpose: Deregulated phosphatidylinositol 3-kinase pathway signaling through AGC kinases including AKT, p70S6 kinase, PKA, SGK and Rho kinase is a key driver of multiple cancers. The simultaneous inhibition of multiple AGC kinases may increase antitumor activity and minimize clinical resistance compared with a single pathway component. Experimental Design: We investigated the detailed pharmacology and antitumor activity of the novel clinical drug candidate AT13148, an oral ATP-competitive multi-AGC kinase inhibitor. Gene expression microarray studies were undertaken to characterize the molecular mechanisms of action of AT13148. Results: AT13148 caused substantial blockade of AKT, p70S6K, PKA, ROCK, and SGK substrate phosphorylation and induced apoptosis in a concentration and time-dependent manner in cancer cells with clinically relevant genetic defects in vitro and in vivo. Antitumor efficacy in HER2-positive, PIK3CA-mutant BT474 breast, PTEN-deficient PC3 human prostate cancer, and PTEN-deficient MES-SA uterine tumor xenografts was shown. We show for the first time that induction of AKT phosphorylation at serine 473 by AT13148, as reported for other ATP-competitive inhibitors of AKT, is not a therapeutically relevant reactivation step. Gene expression studies showed that AT13148 has a predominant effect on apoptosis genes, whereas the selective AKT inhibitor CCT128930 modulates cell-cycle genes. Induction of upstream regulators including IRS2 and PIK3IP1 as a result of compensatory feedback loops was observed. Conclusions: The clinical candidate AT13148 is a novel oral multi-AGC kinase inhibitor with potent pharmacodynamic and antitumor activity, which shows a distinct mechanism of action from other AKT inhibitors. AT13148 will now be assessed in a first-in-human phase I trial. Clin Cancer Res; 18(14); 3912–23. ©2012 AACR.

Despite advances in understanding and treating Prostate Cancer (PCa), there has been little effort to systematically map the biology distinguishing Early-(EOPCa) and Late-(LOPCa) onset PCa. Around 25% of EOPCa cases present with metastatic spread or aggressive disease with earlier metastatic development. Some available lines of therapy are extending treatment trajectories and prolonging lives. However, there remains a critical clinical need to identify new therapeutic targets for EOPCa where life expectancy necessitates safer, more targeted treatment options. To our knowledge, here we present the largest systematic analysis of molecular profiles in EOPCa versus LOPCa, employing machine-learning-enabled algorithms to identify distinguishing biology and druggable targets for each age group. Distinct stromal signatures are uncovered in EOPCa, which are used to propose therapeutic opportunities herein. Moreover, our analysis identifies 50 druggable targets, 11 of which we confirm in PCa cell line genetic/pharmacological perturbation data. These findings provide the first specific, testable hypotheses in EOPCa, offering avenues for experimental validation and potential therapeutic exploitation, and, more generally, shed light on the intricate and distinguished molecular profile of this aggressive, poorly understood disease. One Sentence Summary Machine learning-enabled algorithms were utilized to identify distinguishing biology and associated druggable targets for early-onset prostate cancers. ### Competing Interest Statement BA-L declares financial interest in Recursion Pharmaceuticals, Drug Hunter, and AstraZeneca PLC. BA-L is/has been a member of Scientific Advisory Boards and/or provided paid consultancy for the following: Astex Pharmaceuticals, AstraZeneca PLC, GSK PLC, Novo Nordisk, Sante Ventures. She is a lead on the MD Anderson Drug Discovery and Development Division which has commercial interest in target and drug discovery. She was a chair and member of the Scientific Advisory Board for Open Targets. She is chair of the Cancer Research UK Data Strategy Board and member of the CRUK Scientific Advisory Board. She is a member of the New York Genome Consortium Scientific Advisory Board. She is a member of the Board of Directors of the Leukemia and Lymphoma Society. She is Director of non-profit Chemical Probes Portal. RAE has received honoraria from GU-ASCO, Janssen, University of Chicago, Dana Farber Cancer Institute USA as a speaker. Educational honorarium from Bayer and Ipsen, member of external expert committee to Astra Zeneca UK and Member of Active Surveillance Movember Committee. She is a member of the SAB of Our Future Health. She undertakes private practice as a sole trader at The Royal Marsden NHS Foundation Trust and 90 Sloane Street SW1X 9PQ and 280 Kings Road SW3 4NX, London, UK. PW is or has been a consultant/scientific advisory board member for Alterome Therapeutics, Astex Pharmaceuticals, Black Diamond Therapeutics, CHARM Therapeutics, CV6 Therapeutics, Cyclacel Pharmaceuticals, Epicombi.AI, Merck KGaA, Nuevolution (acquired by Amgen), Nextech Invest, and Vividion Therapeutics (acquired by Bayer AG); has received research funding from Astex Pharmaceuticals, Merck KGaA and Vivan Therapeutics; is a Director of Storm Therapeutics and Derwentwater Associates and a Science Partner at Nextech Invest; holds equity in Alterome Therapeutics, Black Diamond Therapeutics, CHARM Therapeutics, Chroma Therapeutics, Epicombi.AI, Nextech Invest, and Storm Therapeutics; and is a former employee of Zeneca Pharmaceuticals. PW is also Executive Director of the non-profit Chemical Probes Portal. BA-L, ZK-J, AL, BO, QK, SM, CM, and PW are/have been employees of the ICR, which has a Rewards to Inventors scheme and a commercial interest in the development of cancer drug targets. BA-L and STS are employees of UT MD Anderson Cancer Center which operates a reward to inventor scheme.