AZD5991 / AstraZeneca - LARVOL DELTA

A PHASE 1 FIRST-IN-HUMAN STUDY OF THE MCL-1 INHIBITOR AZD5991 IN PATIENTS WITH RELAPSED/REFRACTORY HEMATOLOGIC MALIGNANCIES. (PubMed, Clin Cancer Res) - "Treatment with AZD5991 was associated with high incidence of laboratory troponin elevation and a low overall response rate."

Journal • P1 data • Acute Myelogenous Leukemia • Cardiovascular • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Myelodysplastic Syndrome • Oncology • Respiratory Diseases • Septic Shock

Molecular decoupling of lineage identity and morphology in aggressive variant prostate cancer. (PubMed, medRxiv) - "Pathway and perturbation analyses suggested that NCI-LYM-1 harbored a strong dependency on apoptotic pathways, which was confirmed by in vitro organoid testing with the BCL-2/BCL-xL inhibitor navitoclax (IC 50 : 0.27 µM) and the MCL-1 inhibitor AZD-5991 (IC 50 : 0.060 µM). Overall, NCI-LYM-1 recapitulates the clinical aggressiveness and heterogeneity of AVPC, providing a tractable platform to identify novel precision therapies."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • ASCL1 • BCL2 • BCL2L1 • BRCA2 • PTEN • RB1 • TP53

Molecular subtypes and BH3 mimetic synergy with anti-leukemia agents in T-cell acute lymphoblastic leukemia (ASH 2025) - "In this study, we evaluated the ex vivo cytotoxicity of threeinvestigational BH3 mimetics, namely AZD4320 (BCL2/BCL-XL dual inhibitor), AZ'3202 (BCL-XL inhibitor),and AZD5991 (MCL1 inhibitor), using an imaging-based cell viability assay in a panel of 58 patient-derivedxenograft (PDX) models of T-ALL...These findings highlightthe interplay between molecular subtype and apoptotic signaling and their effects on BH3 mimeticsensitivity in T-ALL.Next, to investigate the therapeutic potential of BH3 mimetics in combination settings for T-ALL, weevaluated the interactions between AZD4320 and key anti-leukemic agents, i.e., asparaginase,prednisolone, nelarabine, and an LCK inhibitor, dasatinib, across 40 T-ALL PDX samples ex vivo...In three T-ALL PDX models, the combination of AZD0466 (a drug-dendrimer conjugateof AZD4320) with asparaginase consistently exhibited greater efficacy compared to monotherapy (vsAZD0466, P = 0.0007, P = 0.015, and P = 0.0006; vs asparaginase, P =..."

Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • T Acute Lymphoblastic Leukemia • T-cell Acute Lymphoblastic Lymphoma • BCL2 • BCL2L1

Beat AML: Study of Biomarker-Based Treatment of Acute Myeloid Leukemia (clinicaltrials.gov) - P1/2 | N=3000 | Recruiting | Sponsor: Beat AML, LLC | N=2000 ➔ 3000 | Trial completion date: Dec 2026 ➔ Dec 2028 | Trial primary completion date: Dec 2026 ➔ Dec 2028

Biomarker • Enrollment change • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Epitranscriptomic signatures define prognosis and therapeutic vulnerabilities in large B-cell lymphoma (ASH 2025) - "The first-line treatment consists of a R-CHOP-like regimen,where 20-40% of patients are refractory to the treatment or will relapse (R/R)...The results showed asynergic effect between the anti-apoptotic protein inhibitors tested and YTHDC1i, particularly with at alow dose of venetoclax (0.01 µM, BCL-2 inhibitor), with a mean of 17% of viability of OCI-LY1 cells, incomparison to venetoclax alone (mean of 35% viability). Interestingly, when the MCL-1 inhibitor (0.1 µM,AZD-5991) was combined with YTHDC1i, we reached a mean of 8% of viability in comparison to MCL-1ialone (mean of 62%)... Our study reveals that specific epitranscriptomic modifications and the expression of theirregulatory enzymes are significantly associated with overall survival in patients with LBCL. Among these,i6A and its writer, TRIT1, correlate with a better prognosis, while m1G and m1A, along with theirassociated enzymes, predict poorer outcomes. Functional assays identified YTHDC1 as a..."

IO biomarker • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Large B Cell Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • ALKBH5 • ANXA5 • BCL2L1 • CASP3 • METTL1 • METTL3 • TRMT6 • WDR4 • YTHDC1

CSF1R-CSF1 axis blockade with axatilimab effectively targets leukemia stem cells and monocytes in AML resistant to BH3 mimetics (ASH 2025) - "Background : The BCL2 inhibitor venetoclax (VEN), in combination with hypomethylating agents, ishighly effective in inducing remissions in AML...The effects on cytokine production, AML blasts, stem cells, andmonocytes were evaluated. MV4-11 cells with acquired resistance to BH3 mimetics targeting BCL2 or MCL1,peculiarly to VEN and VEN plus MCL-1 inhibitor AMG176, exhibited elevated levels of cytokinesincluding CSF1, TGF-1ß, IL-4, and IL-10 compared to parental cells... CSF1, TGF-1ß, IL-4, IL-10, and numerous other cytokines are increased in BH3mimetic resistant AML cell lines and patient samples. Inhibition of CSF1R targets ERK and AKTsignaling and significantly enhances the cytotoxic effects of BH3 mimetics against AML cells,stem/progenitor cells, and monocytes resistant to VEN. Furthermore, blockage of CSF1R-CSF1axis suppresses multiple cytokines in vitro and in vivo, and markedly improves the therapeuticefficacy of BH3 mimetics in a VEN/AZD5991/Decitabine..."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • ANXA5 • CSF1R • IL10 • IL4 • TP53

Inhibition of NSD2 in t(4; 14) myeloma induces changes in mitochondrial priming (ASH 2025) - "Dynamic profilingof KMS11 indicated increased priming on BCL-XL and potentially BCL2 with delta priming of 14-21% withBAD and 14% with HRK peptides (targets BCL-XL), as well as increased sensitivity to AZD4320 and DT2216(BCL-XL PROTAC)...Additionally, we found these cells were less sensitive to AZD5991 and AZD4320 thanthe control cells, suggesting loss of NDS2 in KMS18 leads to decreased priming. Dynamic mitochondrial profiling post-NSD2 inhibition in t(4; 14) myeloma displayed cell linespecific patterns, perhaps owing to the heterogenous baseline priming in this high-risk subtype... Dynamic mitochondrial profiling post-NSD2 inhibition in t(4; 14) myeloma displayed cell linespecific patterns, perhaps owing to the heterogenous baseline priming in this high-risk subtype. Themolecular basis for these differences is under current investigation and could be related to thedifferences in genes influenced by NSD2 activity in these cells. RNAseq analysis of 3 myeloma cells..."

IO biomarker • Hematological Malignancies • Multiple Myeloma • Targeted Protein Degradation • ANXA5 • BCL2L1 • FGFR3 • NSD2 • TP53

FLT3L-based conjugate targets chemoresistant leukemia stem cells via cell cycle re-entry in Acute Myeloid Leukemia [WITHDRAWN] (ASH 2025) - "FL-Fc-DM1 outperformed unconjugated DM1 in vitro, remained effective inthe presence of physiological FLT3L, induced FLT3 internalization, and activated the p53 pathway.Cytarabine treatment induces a senescence-like phenotype in AML characterized by G1 arrest andupregulation of senescence-associated genes, which confer resistance...Co-treatment with the MCL1 inhibitor AZD-5991 or the BCL2inhibitor venetoclax synergistically enhanced cell death, particularly in FLT3-ITD-positive AML cells...Serial transplantation and limitingdilution assays demonstrated that FL-Fc-DM1 selectively depleted LSCs, impairing leukemia-initiatingpotential.Importantly, at therapeutically relevant concentrations, FL-Fc-DM1 selectively suppressed colonyformation of AML-derived CD34⁺ cells while sparing healthy donor CD34⁺ hematopoietic stem cells exvivo. Consistently, in a humanized mouse model reconstituted with healthy human CD34⁺ cells, FL-Fc-DM1 treatment preserved normal hematopoiesis, immune..."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • CD34 • FLT3 • PTPRC

Synergy between enzalutamide and selective Bcl-2 family inhibitors in metastatic castration-resistant prostate cancer (ESMO Asia 2025) - "While venetoclax (Bcl-2 inhibitor) combinations with enzalutamide have entered clinical evaluation, the relative benefit of inhibiting different Bcl-2 family members under identical experimental conditions has not been directly compared. DU145 mCRPC cells were treated for 48 h with enzalutamide (ENZA) alone or in combination with ABT-199 (Bcl-2 inhibitor), A-1331852 (Bcl-xL inhibitor), or AZD5991 (Mcl-1 inhibitor). In a direct comparison under uniform conditions, Mcl-1 inhibition with AZD5991 emerged as the most effective partner for ENZA in DU145 cells, followed by Bcl-xL inhibition, while Bcl-2 inhibition was less impactful. These findings support further evaluation of Mcl-1-targeting strategies as a means to overcome AR-independent resistance in mCRPC, while underscoring the need for cautious interpretation of large in-vitro dose-reduction estimates."

IO biomarker • Metastases • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • ANXA5 • BCL2L1

Proteasome inhibition as a potential therapeutic target in thymic cancer. (PubMed, Cell Death Dis) - "Carfilzomib synergized with BCL2 family protein inhibitors (navitoclax or AZD5991), suggesting that drug combinations could be used to reduce the dose of each drug to minimize toxicity. Notably, thymic carcinomas differed from squamous cell carcinomas in other organs by higher levels of β5i (PSMB8) and constitutive proteasome β5 (PSMB5). We hypothesize that TC (and probably many TH) are uniquely suited for treatment with proteasome inhibitors alone or in combination with selective BH3 mimetics."

IO biomarker • Journal • Oncology • Solid Tumor • Squamous Cell Carcinoma • Thymic Carcinoma • Thymic Epithelial Tumor • Thymoma • Thymus Cancer • BCL2 • PSMB10 • PSMB5 • PSMB8 • PSMB9

The development of ACT001 with Mcl-1 inhibitors as a novel combination therapy for the treatment of paediatric diffuse midline glioma (SNO 2025) - P1 | "Among the strongest were Mcl-1 inhibitors (Mcl1i-MIK665, Mcl1i-AZD5991) consistent with ACT001's mechanism of downregulating anti-apoptotic signaling...In vivo, single-drug treatment of ACT001 or Mcl1i-S63845 extended survival in orthotopic DMG models and significantly reduced the number of Ki67-positive tumor cells...Our findings suggest that ACT001 is a multi-targeted agent acting on NF-κB and apoptotic signalling while inducing oxidative stress. The combination of ACT001 with anti-apoptotic protein inhibitors represents a promising treatment strategy for DMG patients."

Combination therapy • IO biomarker • Brain Cancer • Diffuse Midline Glioma • Glioblastoma • Glioma • Pediatrics • Solid Tumor • BCL2 • NQO1 • SLC7A11 • SOD2

Impact of Docirbrutinib (AS-1763) Treatment in CLL: Preclinical Data and Early Clinical Biomarkers (ASH 2024) - P1 | "Biological and biochemical effects were tested in treatment-naïve (TN with BTK-wild type) and relapsed/refractory (R/R with BTK and/or Bcl-2 mutant) CLL cells during in vitro investigations with 0.01, 0.1, and 1 µM docirbrutinib alone or with Bcl-2i (venetoclax) or Mcl-1i (AZD5991)...In TN CLL lymphocytes from 11 CLL pts, 72-hr incubation with docirbrutinib induced modest yet significant apoptosis which was comparable to ibrutinib or pirtobrutinib...In the dose-escalation trial, docirbrutinib treatment showed decreased BCR pathway biomarkers such as CCL3/CCL4 and phospho-BTK and PLCγ2. Updated data will be presented."

IO biomarker • Preclinical • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • BCL2L1 • CCL3 • CD86 • CXCL12 • PLCG2

Advances in the Management of Relapsed/Refractory CLL and Richter Transformation (ICML 2025) - P=N/A, P2, P3 | "BRUIN CLL-321 is a phase 3, registrational study that evaluated pirtobrutinib compared to the investigator's choice of idelalisib plus rituximab (IdelaR) or bendamustine plus rituximab (BR) [23]...Nemtabrutinib is now being evaluated in the registrational, phase 3 BELLWAVE-010 trial (NCT05947851) for patients with R/R CLL, comparing nemtabrutinib plus venetoclax to venetoclax plus rituximab...An ongoing, open-label, first-in-human phase 1/2 study is evaluating the BTK degrader BGB-16673 as monotherapy in patients with R/R CLL [27, 28]...NX-2127 is an investigational, first-in-class BTK degrader currently being evaluated in a phase 1 trial for patients with relapsed or refractory B-cell malignancies, CLL [29, 30]...NX-5948 is another investigational and more selective BTK degrader in an ongoing Phase 1a/1b clinical trial...This trial aims to establish lisaftoclax plus acalabrutinib as a potential alternative to venetoclax-based BTKi combination..."

IO biomarker • Acute Myelogenous Leukemia • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Non-Hodgkin’s Lymphoma • Oncology • Richter's Syndrome • Small Lymphocytic Lymphoma • BCL2L1 • TP53

The development of ACT001 with Mcl-1 inhibitors as a novel combination therapy for the treatment of paediatric diffuse midline glioma (WFNOS 2025) - P1 | "Among the strongest were Mcl-1 inhibitors (Mcl1i-MIK665, Mcl1i-AZD5991) consistent with ACT001’s mechanism of downregulating anti-apoptotic signaling...In vivo, single-drug treatment of ACT001 or Mcl1i-S63845 extended survival in orthotopic DMG models and significantly reduced the number of Ki67-positive tumor cells...Our findings suggest that ACT001 is a multi-targeted agent acting on NF-κB and apoptotic signalling while inducing oxidative stress. The combination of ACT001 with anti-apoptotic protein inhibitors represents a promising treatment strategy for DMG patients."

Combination therapy • IO biomarker • Brain Cancer • Diffuse Midline Glioma • Glioblastoma • Glioma • Pediatrics • Solid Tumor • BCL2 • NQO1 • SLC7A11 • SOD2

Identification of vulnerabilities for targeting BCL-2 family members in T-Cell Acute Lymphoblastic Leukemia (ASH 2023) - "Venetoclax is a selective BCL-2 inhibitor and is successfully used in CLL and AML, but heterogeneous sensitivity to venetoclax has been described in ALL and inhibitors of other BCL-2 family members including BCL-XL-selective A-1331852 and MCL-1 selective AZD5991 have been developed. Moreover, a dual inhibitor of the anti-apoptotic BCL-2 family members BCL-2 and BCL-XL (AZD4320) with its dendrimer conjugate (AZD0466) has recently shown anti-tumor activity in hematologic cancer models with manageable toxicity...Taken together, we found vulnerabilities of T-ALL to BCL-2 family inhibition, particularly to dual BCL-2/BCL-XL inhibition by AZD4320, and we demonstrated on-target activities. Using BH3-profiling, we identified BAD-priming as a marker of response for AZD4320 and MCL-1 dependence as a resistance mechanism that can be targeted by combination treatment, suggesting further clinical evaluation."

IO biomarker • Acute Lymphocytic Leukemia • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Acute Lymphoblastic Leukemia • T-cell Acute Lymphoblastic Lymphoma • BCL2 • BCL2L1

AZD4573 in Combination with CHOP Increases Combination Benefit in Preclinical Peripheral T-Cell Lymphomas Models (ASH 2023) - P2 | "Current standard of care for pTCL revolves around the chemotherapy regimens CHOP/E and for CD30-postive pTCLs, brentuximab vedotin is approved...Using the MCL-1 inhibitor AZD5991, we have shown statistically significant benefit in survival when combined with CHOP in 2 MCL-1 dependent preclinical pTCL PDX models (Koch et al...These data suggested that treatment with AD4573 either as a monotherapy or in combination with CHOP, would be an effective therapeutic strategy in pTCL. AZD4573 monotherapy is currently being evaluated in a phase 2 study (NCT05140382) to assess the efficacy, safety, and PK in patients with relapsed/refractory pTCL."

Combination therapy • IO biomarker • Preclinical • Cutaneous T-cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • BCL2 • BCL2A1 • BCL2L1 • CASP3 • CASP7 • MYC • TNFRSF8

Drug Resistance Can be Overcome in Multiple Myeloma and Acute Myeloid Leukemia By Targeting Mcl-1 with the Small Chemical KS18 (ASH 2023) - "5µM, KS18 demonstrated efficacy against bortezomib-resistant MM cells, outperforming other Mcl-1 inhibitors in clinical trials such as S63845, VU661013, and AZD5991. According to these results, KS18 may be able to overcome resistance by concentrating on Mcl-1. These encouraging findings have prompted the development of many models of drug-resistant MM and AML for in vivo evaluation of this potential chemical."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology • BCL2

Targeting MCL-1 to Overcome Therapeutic Resistance and Improve Cancer Mortality. (PubMed, Health Sci Rep) - "The structural foundations for the design of MCL-1 inhibitors are revisited, the pharmacological profiles of the leading drugs (S63845, AZD5991, AMG 176) in advanced clinical development are summarized, and emerging strategies, such as combination therapies with inhibitors of anti-apoptotic proteins such as BCL-2, PROTAC strategies designed to degrade MCL-1, and reversible-binding chemotypes to maximize MCL-1 inhibition and minimize toxicity, are reviewed. The key to clinical success will be to carefully develop more intensive dosing regimens, rationally combine agents, and develop trial designs that prioritize the evaluation of new agents that maximize antitumor activity without the risk of off-target toxicities. Continued translational research and adaptive clinical trials are critical to fully realize the therapeutic potential of MCL-1 inhibition across various cancer contexts."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Immune Modulation • Immunology • Leukemia • Lung Cancer • Multiple Myeloma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • BCL2

Immunogenic cell death-related genes as prognostic biomarkers and therapeutic insights in uterine corpus endometrial carcinoma: an integrative bioinformatics analysis. (PubMed, Front Oncol) - "Finally, we found that hyper-immunogenicity may be sensitive to immunotherapy and certain drugs (AZD5991, Ibrutinib, Osimertinib, AGI-5198, Savolitinib, Sapitinib, AZ960, AZD3759 and Ruxolitinib), while PCI-34051 and Vorinostat showed sensitivity in patients with hypo-immunogenicity. Our results demonstrate that ICD plays an important role in UCEC progression, suggesting that ICD-related markers could serve as potential targets for prognosis and treatment."

Biomarker • IO biomarker • Journal • Tumor mutational burden • Endometrial Cancer • Oncology • Solid Tumor • Uterine Cancer • CD52 • STAT1 • TMB

Combining MCL-1 inhibition and CD37-directed chimeric antigen receptor T cells as an effective strategy to target T-cell lymphoma. (PubMed, Leukemia) - "In TCL models with dependence on MCL-1, combining CAR-37 T cells and the MCL-1 inhibitor AZD5991 increases anti-TCL response and prolongs survival of xenografted mice. These findings suggest that personalized selection of BH3 mimetic/CAR-T combinations could maximize the therapeutic index for patients with TCL and possibly other diseases."

IO biomarker • Journal • Hematological Malignancies • Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • CD37

Bim and Mcl-1 Coordinate NVP-BEZ235-induced Renal Cell Carcinoma Cell Apoptosis. (PubMed, Arch Biochem Biophys) - "Bcl-2 inhibitor ABT-737 and Mcl-1 inhibitor AZD5991 predisposed NVP-BEZ235-treated cells to transform into the apoptotic phenotype. PI3K inhibitor LY294002 and Stat3 inhibitor AG490 duplicated the sensitized actions towards NVP-BEZ235...Data of in vivo tumor-bearing studies further revealed a better anti-tumor potential in the combination treatment of NVP-BEZ235 and MEK/ERK inhibitors without obvious toxicity. Our findings suggest that the feedback activation of pro-survival machinery is likely to be the main cause of cancer cells being refractory to NVP-BEZ235, and a combination treatment is a feasible strategy to sensitize cancer cell responses."

IO biomarker • Journal • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Targeted Protein Degradation • BCL2L11 • MCL1

Repurposing AZD-5991 for inhibiting growth and biofilm formation of Staphylococcus aureus by disrupting the cell membrane and targeting FabI. (PubMed, BMC Microbiol) - No abstract available

Journal

INHIBITION OF CSF1R-CSF1 AXIS WITH AXATILIMAB EFFECTIVELY TARGETS LEUKEMIA STEM CELLS AND MONOCYTES IN BH3 MIMETICS-RESISTANT AML (EHA 2025) - "Background: BCL2 inhibitor venetoclax (VEN)/hypomethylating agent regimen are highly effective in inducing remissions in AML. We demonstrate that inhibition of CSF1R enhances the cytotoxic activities of BH3 mimetics and is highly active in combination with both BH3 mimetics against AML cells and stem/progenitor cells resistant to VEN. Targeting CSF1R-CSF1 axis suppresses multiple cytokines in vitro and in vivo, and significantly enhances the therapeutic efficacy of BH3 mimetics in a VEN/AZD5991/Decitabine triple resistant PDX model."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Oncology • ANXA5 • CSF1R • IL10 • IL4 • IL6 • TP53

ASSESSING THE EFFICACY OF NK CELLS IN COMBINATION WITH BH3-MIMETICS IN T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (EHA 2025) - "To assess sensitivity of T-ALL for BH3-mimetics, we performed EC50 measurements for the BH3-mimetics venetoclax (BCL-2), A1331852 (BCL-XL), AZD4320 (BCL-2/BCL-XL) and AZD5991 (MCL-1). Taken together, we found heterogeneous sensitivity of T-ALL to NK cells and BH3-mimetics. These sensitivities were reflected in BH3-profiling assays, providing a potential marker of response. Combining NK cells with BH3-mimetics improved cell killing efficacy, suggesting further preclinical and potential clinical evaluation."

Clinical • Combination therapy • IO biomarker • Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Pediatrics • T Acute Lymphoblastic Leukemia • T-cell Acute Lymphoblastic Lymphoma • Thrombocytopenia • BCL2 • BCL2L1 • IL15 • MCL1

Potential novel interventions of oncohistones, epigenetic modifications, and RNA processing machinery in betel-nuts related HNSCC in Taiwan (AACR 2025) - "PI3K/AKT/mTOR interventions, ALK/IGF1R inhibitor, CDK4/6 inhibitor, BCl2 inhibitor, WEE1 inhibitor, ATR inhibitor, DNA-PK inhibitor, AT2AR inhibitor, Mcl-1 inhibitor, MEK1/2 inhibitor, JAK2 inhibitor, CXCR4 inhibitor, FAK inhibitor, p53 reactivator, MDM2 inhibitor, SHP2 inhibitor, PARP7 inhibitor, IAP inhibitor, GLS1 inhibitor, eribulin, & VEGFR2/ PDGFR/FGFR or VEGFR2/c-MET/Axl triple blockage might be effective on TW2.6 and reverse treatment refractoriness, through the inhibition of mesenchymal transformation, pRB, & PI3K/AKT /mTOR signaling and modulation of stemness & PD1/PDL1 pathway...Disrupting NSD1 in HNSCC cell lines led to CpG hypomethylation & enhanced cisplatin sensitivity. TW2.6 used to test (1)in vitro drug sensitivity to (a)Chemical Modulators of Splicing; (b)PRMT5 inhibitor; (c)CDK9 inhibitor, EZH2i, DNMT3i, BRD/BET4i, and HDACi; (d)NSD1/SETD2 inhibitor; (e)METTL3 inhibitor; (2)synergistic effects with other therapies by MTT assay, colony..."

IO biomarker • Head and Neck Cancer • Oncology • Squamous Cell Carcinoma of Head and Neck • AKT1 • ALK • ARID1B • ATM • AXL • BRD4 • CCND3 • CDK12 • CXCR4 • DDR2 • EPHB1 • FAT1 • FGF10 • FGFR • FLCN • HRAS • KDM5A • KDR • METTL3 • MITF • NSD1 • PDGFRB • PIK3CA • RICTOR • RPS6KB1 • SDHA • SETD2 • SOX9 • STK11 • TERT • TIPARP • TMB • TNFAIP3