CDK4/6 inhibition stabilizes disease in patients with p16-null non-small cell lung cancer and is synergistic with mTOR inhibition
| Autor: | Alison Marguerite Ivey, Mary Pinder-Schenck, Frederic J. Kaye, Andres Gordillo Villegas, Maria Zajac-Kaye, Alberto Chiappori, Wei Hou, Chunxia Cao, Priya K. Gopalan |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
palbociclib Phases of clinical research Palbociclib 03 medical and health sciences chemistry.chemical_compound CDK 4/6 0302 clinical medicine Clinical endpoint Medicine Lung cancer PI3K/AKT/mTOR pathway non-small cell lung cancer business.industry clinical trial medicine.disease 3. Good health 030104 developmental biology Oncology chemistry Tumor progression 030220 oncology & carcinogenesis Cancer research mTOR Growth inhibition CDK4/6 Inhibition business Priority Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | Aberrant activation of CDK4/6 kinase is the most common somatic event in non-small cell lung cancer (NSCLC). Palbociclib is a highly specific CDK4/6 inhibitor shown to inhibit cell cycle progression and promote cellular senescence. We conducted a phase 2 clinical trial of palbociclib in 19 previously-treated patients with advanced NSCLC. Only patients with p16-null staining by immunohistochemistry and documented tumor progression were eligible. The primary endpoint was tumor response rate. Palbociclib therapy alone was well-tolerated. Of 16 evaluable patients who received > 1 month of therapy, there were no objective responses. However, 8 patients (50%) with previously progressive NSCLC had stable disease (SD) lasting a range of 4-10.5 months. Median overall survival (OS) for all cases was 5.1 months, and median overall survival for the subset of patients with SD was 16.6 months. We also performed preclinical testing of palbociclib in combination with 13 different targeted or cytotoxic chemotherapeutic agents using a cell viability assay. Only the combination of palbociclib and mTOR inhibitors resulted in synergistic growth inhibition, particularly in tumors carrying RAS mutations. Our findings warrant further clinical investigation of the combination of palbociclib and mTOR inhibitors, especially in patients carrying activated RAS mutations. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|