ArticleClinical cancer research : an official journal of the American Association for Cancer Research2023
BBT-176, a Novel Fourth-Generation Tyrosine Kinase Inhibitor for Osimertinib-Resistant EGFR Mutations in Non-Small Cell Lung Cancer.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT04820023 (A Phase 1/2, Open-Label Study to Assess the Safety, Tolerability, Pharmacokinetics, and Anti-tumor Activity of BBT-176 in Patients With Advanced Non-Small Cell Lung Cancer), which is not on this map. Cited by 44 papers, 1 of them a synthesis that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Phase 1/2, Open-Label Study to Assess the Safety, Tolerability, Pharmacokinetics, and Anti-tumor Activity of BBT-176 in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC) Who Progressed Following Prior Therapy With an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR TKI) Agent
Who cites it
44 citing papers in PubMed, 1 synthesis or guideline pooled it, 71 citations in OpenAlex.
- Pooled it
- Targeting ClassicalCancers · 2026Review
- JIN-A02, a Mutant-Selective Fourth-Generation EGFR Inhibitor, Overcomes C797S-Mediated Resistance and Demonstrates Intracranial Activity in NSCLC.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Article
- Precision Medicine in Treating Lung Cancer: A Narrative Review on Treatments Targeting Oncogenic Genetic Mutations.Cureus · 2026Review
- The resistance landscape of EGFR tyrosine kinase inhibitors in advanced non-small cell lung cancer: molecular mechanisms and novel therapeutic strategies.Translational lung cancer research · 2026Review
- Durvalumab Plus Chemotherapy in Patients WithJTO clinical and research reports · 2026Article
- Lactylation-related gene signature for prognosis prediction and immune infiltration assessment in lung adenocarcinoma via bulk and single-cell RNA sequencing.Discover oncology · 2026Article
- Huaier Aqueous Extract Combined with Gefitinib Promotes ACSL4-Dependent Ferroptosis and Overcomes Gefitinib Resistance in Non-Small Cell Lung Cancer.Current medical science · 2026Article
- Targeting PLK1 potentiates the antitumor efficacy of EGFR-TKIs through inhibiting the JAK1/STAT3 pathway.Cell death & disease · 2026Article
- Prognostic value of baselineFrontiers in nuclear medicine · 2026Article
- Navigating the landscape of EGFR TKI resistance in EGFR-mutant NSCLC - mechanisms and evolving treatment approaches.Nature reviews. Clinical oncology · 2026Review
- Medicinal Chemistry of Fourth-generation Tyrosine Kinase Inhibitors.Mini reviews in medicinal chemistry · 2026Review
- Resistance to third-generation EGFR TKIs - what can be expected from the fourth-generation?Cancer drug resistance (Alhambra, Calif.) · 2026Review
- Advances in understanding the mechanisms underlying acquired resistance to third-generation tyrosine kinase inhibitors in non-small cell lung cancer.Frontiers in cell and developmental biology · 2026Review
- Fourth-generation EGFR-TKI to overcome C797S mutation: past, present, and future.Journal of enzyme inhibition and medicinal chemistry · 2025Review
- Berberine: a promising strategy to combat cetuximab-resistance in colorectal cancer.BMC cancer · 2025Article
- Lung cancer in non-smoking women (LCINSW): from risk factors to precision therapy.Cancer metastasis reviews · 2025Review
- Current and Emerging Therapies for Targeting the ERK1/2 & PI3K Pathways in Cancer.International journal of molecular sciences · 2025Review
- EGFR: New Insights on Its Activation and Mutation in Tumor and Tumor Immunotherapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- The inhibitory effect of tyrosine kinase inhibitors on angiogenesis in zebrafish and interrelationship with the activation of the PI3K/AKT pathway.BMC pharmacology & toxicology · 2025Article
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Authors and funding
10 authors at 7 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposeResistance to third-generation EGFR inhibitors including osimertinib arises in part from the C797S mutation in EGFR. Currently, no targeted treatment option is available for these patients. We have developed a new EGFR tyrosine kinase inhibitor (TKI), BBT-176, targeting the C797S mutation. PATIENTS AND
methodsRecombinant EGFR proteins and Ba/F3 cell lines, patient-derived cells, and patient-derived xenografts expressing mutant EGFRs were used to test the inhibitory potency and the anticancer efficacy of BBT-176 both in vitro and in vivo. Patient case data are also available from an ongoing phase I clinical trial (NCT04820023).
resultsThe half maximal inhibitory concentration (IC50) of BBT-176 against EGFR 19Del/C797S, EGFR 19Del/T790M/C797S, and EGFR L858R/C797S proteins were measured at 4.36, 1.79, and 5.35 nmol/L, respectively (vs. 304.39, 124.82, and 573.72 nmol/L, for osimertinib). IC50 values of BBT-176 against Ba/F3 cells expressing EGFR 19Del/C797S, EGFR 19Del/T790M/C797S, EGFR L858R/C797S, and EGFR L858R/T790M/C797S were 42, 49, 183, and 202 nmol/L, respectively (vs. 869, 1,134, 2,799, and 2,685 nmol/L for osimertinib). N-ethyl-N-nitrosourea mutagenesis suggested that BBT-176 treatment does not introduce any secondary mutations in the EGFR gene but increases EGFR expression levels. Combined with the EGFR antibody cetuximab, BBT-176 effectively suppressed the growth of BBT-176-resistant clones. BBT-176 strongly inhibited the tumor growth, and in some conditions induced tumor regression in mouse models. In the clinical trial, two patients harboring EGFR 19Del/T790M/C797S in blood showed tumor shrinkage and radiologic improvements.
conclusionsBBT-176 is a fourth-generation EGFR inhibitor showing promising preclinical activity against NSCLC resistant to current EGFR TKI, with early clinical efficacy and safety.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.