NVP-ADW742 / Novartis - LARVOL DELTA

Combinatorial CRISPR screen reveals FYN and KDM4 as targets for synergistic drug combination for treating triple negative breast cancer. (PubMed, Elife) - "By employing pairwise tyrosine kinase knockout CRISPR screens, we identify FYN and KDM4 as critical targets whose inhibition enhances the effectiveness of TKIs, such as NVP-ADW742 (IGF-1R inhibitor), gefitinib (EGFR inhibitor), and imatinib (ABL inhibitor) both in vitro and in vivo. FYN expression is associated with therapy resistance and persistence by demonstrating its upregulation in various experimental models of drug-tolerant persisters and residual disease following targeted therapy, chemotherapy, and radiotherapy. Collectively, our study provides novel targets and mechanistic insights that can guide the development of effective combinatorial targeted therapies, thus maximizing the therapeutic benefits of TKIs."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • FYN

Establishment and characterization of amitrole-induced mouse thyroid adenomatous nodule-derived cell lines. (PubMed, Thyroid) - "Signal transduction and cell proliferation were evaluated after treatment with insulin-like growth factor-I (IGF-I) and the selective IGF-I receptor (IGF-IR) inhibitor NVP-ADW742...They lacked tumorigenicity and prominent gene mutations involved in thyroid cancer development, while missense mutations were found in some tumor suppressors as revealed by WGS. The CAT458s and 459 provide a new tool to further clarify the process of thyroid multi-step carcinogenesis and differentiation."

Journal • Preclinical • Endocrine Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma • BRAF • IGF1 • POLK • TERT • TGFB1 • TP53

IGF1R as a Potential Pharmacological Target in Allergic Asthma. (PubMed, Biomedicines) - "Our results demonstrate that IGF1R could be considered a potential pharmacological target in murine HDM-induced asthma and a candidate biomarker in allergic asthma."

Journal • Allergy • Asthma • Eosinophilia • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • IGF1R

IGF-1R depletion sensitizes colon cancer cell lines to radiotherapy. (PubMed, Cancer Biomark) - "Our findings demonstrate that depletion of IGF-1R lead to an increase in radiosensitivity in CRC."

Journal • Preclinical • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • HRD • RAD51 • TP53BP1

Systematic prediction of drug resistance caused by transporter genes in cancer cells. (PubMed, Sci Rep) - "Novel drug-transporter interactions were discovered, such as lapatinib and gefitinib with ABCA1, olaparib and NVPADW742 with ABCC3, and gefitinib and AZ628 with SLC4A4. Furthermore, we identified ABCC3, SLC12A7, SLCO4A1, SERPINA1, and SLC22A3 as potential transporters for erlotinib, three of which are also significantly more highly expressed in patients who were resistant to therapy in a clinical trial."

Journal • Oncology • ABCC3 • SLC22A3 • SLC2A3 • SLC4A4

Targeting Insulin-Like Growth Factor 1 Receptor Delays M-Phase Progression and Synergizes with Aurora B Inhibition to Suppress Cell Proliferation. (PubMed, Int J Mol Sci) - "Moreover, a similar delay in M phase was observed following 2 h of incubation with the IGF1R inhibitors OSI-906 and NVP-ADW742. Live-cell imaging revealed that both prolonged prometaphase and prolonged metaphase underlie the delay and this can be abrogated by the inhibition of Mps1 with AZ3146, suggesting activation of the Spindle Assembly Checkpoint when IGF1R is inhibited. Furthermore, incubation with the Aurora B inhibitor ZM447439 potentiated the IGF1R inhibitor-induced suppression of cell proliferation, opening up new possibilities for more effective cancer chemotherapy."

Journal • Oncology

The cytoskeleton actin binding protein filamin A impairs both IGF2 mitogenic effects and the efficacy of IGF1R inhibitors in adrenocortical cancer cells. (PubMed, Cancer Lett) - "In addition, FLNA knockdown potentiated antiproliferative effects of IGF1R/IR inhibitor Linsitinib and IGF1R inhibitor NVP-ADW742 in H295R. Finally, Western blot showed lower FLNA expression in ACCs (n = 10) than in ACAs (n = 10) and an inverse correlation of FLNA/IGF1R ratio with ERK phosphorylation in ACCs only. In conclusion, we demonstrated that low FLNA levels enhance both IGF2 proliferative effects and IGF1R/IR inhibitors efficacy in ACC cells, suggesting FLNA as a new factor influencing tumor clinical behavior and the response to the therapy with IGF1R/IR-targeted drugs."

Clinical • Journal • Genito-urinary Cancer • Melanoma • Oncology • Solid Tumor • IGF2

[VIRTUAL] The Role of Filamin A (FLNA) in the Regulation of Insulin-Like Growth Factor System in Adrenocortical Carcinomas (ENDO-I 2020) - "In addition, FLNA knockdown potentiated the antiproliferative effects of IGF1R/IR inhibitor Linsitinib and IGF1R specific inhibitor NVP-ADW742 in H295R cells and SW13. Interestingly, FLNA/IGF1R ratio inversely correlated with ERK phosphorylation status in ACCs (p<0.05) but not in ACA. In conclusion, we demonstrated that low levels of FLNA enhance both IGF2 proliferative effects and IGF1R/IR inhibitors efficacy in ACC cells, suggesting FLNA as a new factor possibly influencing tumor clinical behavior and the response to the therapy with IGF1R/IR-targeted drugs."

Genito-urinary Cancer • Melanoma • Oncology • Solid Tumor • IGF1R • IGF2

The Role of Filamin A (FLNA) in the Regulation of Insulin-Like Growth Factor System in Adrenocortical Carcinomas (ENDO 2020) - "In addition, FLNA knockdown potentiated the antiproliferative effects of IGF1R/IR inhibitor Linsitinib and IGF1R specific inhibitor NVP-ADW742 in H295R cells and SW13. Interestingly, FLNA/IGF1R ratio inversely correlated with ERK phosphorylation status in ACCs (p<0.05) but not in ACA. In conclusion, we demonstrated that low levels of FLNA enhance both IGF2 proliferative effects and IGF1R/IR inhibitors efficacy in ACC cells, suggesting FLNA as a new factor possibly influencing tumor clinical behavior and the response to the therapy with IGF1R/IR-targeted drugs."

IGF1R • IGF2

The Role of Filamin A (FLNA) in the Regulation of Insulin-Like Growth Factor System in Adrenocortical Carcinomas (ENDO 2020) - "In addition, FLNA knockdown potentiated the antiproliferative effects of IGF1R/IR inhibitor Linsitinib and IGF1R specific inhibitor NVP-ADW742 in H295R cells and SW13. Interestingly, FLNA/IGF1R ratio inversely correlated with ERK phosphorylation status in ACCs (p<0.05) but not in ACA. In conclusion, we demonstrated that low levels of FLNA enhance both IGF2 proliferative effects and IGF1R/IR inhibitors efficacy in ACC cells, suggesting FLNA as a new factor possibly influencing tumor clinical behavior and the response to the therapy with IGF1R/IR-targeted drugs."

IGF1R • IGF2

The IGF-1R Inhibitor NVP-ADW742 Sensitizes Radioresistant Human Colorectal Cancer to Radiotherapy (ASCRS 2019) - "(D) Immunoblots assessing the level of gamma-H2AX in SW480 and HT-29 cells with indicated treatments. All experiments were performed in triplicate (n = 3)."