byl719 and palbociclib

byl719 has been researched along with palbociclib* in 2 studies

Other Studies

2 other study(ies) available for byl719 and palbociclib

ArticleYear
Alpelisib combination treatment as novel targeted therapy against hepatocellular carcinoma.
    Cell death & disease, 2021, 10-08, Volume: 12, Issue:10

    Hepatocellular carcinoma (HCC) is the sixth most common primary cancer with an unsatisfactory long-term survival. Gain of function mutations of PIK3CA occur in a subset of human HCC. Alpelisib, a selective PIK3CA inhibitor, has been approved by the FDA to treat PIK3CA mutant breast cancers. In this manuscript, we evaluated the therapeutic efficacy of alpelisib, either alone or in combination, for the treatment of HCC. We tested alpelisib in mouse HCC induced by hydrodynamic injection of c-Met/PIK3CA(H1047R) (c-Met/H1047R), c-Met/PIK3CA(E545K) (c-Met/E545K), and c-Met/sgPten gene combinations. Alpelisib slowed down the growth of c-Met/H1047R and c-Met/E545K HCC but was ineffective in c-Met/sgPten HCC. Mechanistically, alpelisib inhibited p-ERK and p-AKT in c-Met/H1047R and c-Met/E545K HCC progression but did not affect the mTOR pathway or genes involved in cell proliferation. In human HCC cell lines transfected with PIK3CA(H1047R), alpelisib synergized with the mTOR inhibitor MLN0128 or the CDK4/6 inhibitor palbociclib to suppress HCC cell growth. In c-Met/H1047R mice, alpelisib/MLN0128 or alpelisib/palbociclib combination therapy caused tumor regression. Our study demonstrates that alpelisib is effective for treating PIK3CA-mutated HCC by inhibiting MAPK and AKT cascades. Furthermore, combining alpelisib with mTOR or CDK4/6 inhibitors has a synergistic efficacy against PIK3CA-mutated HCC, providing novel opportunities for precision medicine against HCC.

    Topics: Anilides; Animals; Benzoxazoles; Carcinogenesis; Carcinoma, Hepatocellular; Cell Line, Tumor; Class I Phosphatidylinositol 3-Kinases; Disease Models, Animal; Female; Humans; Liver Neoplasms; MAP Kinase Signaling System; Mice; Molecular Targeted Therapy; Mutation; Piperazines; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-met; PTEN Phosphohydrolase; Pyridines; Pyrimidines; Thiazoles; Treatment Outcome; Tumor Burden

2021
ER+ Breast Cancer Strongly Depends on MCL-1 and BCL-xL Anti-Apoptotic Proteins.
    Cells, 2021, 07-02, Volume: 10, Issue:7

    Breast cancer is the most frequent type of cancer and the major cause of mortality in women. The rapid development of various therapeutic options has led to the improvement of treatment outcomes; nevertheless, one-third of estrogen receptor (ER)-positive patients relapse due to cancer cell acquired resistance. Here, we use dynamic BH3 profiling (DBP), a functional predictive assay that measures net changes in apoptotic priming, to find new effective treatments for ER+ breast cancer. We observed anti-apoptotic adaptations upon treatment that pointed to metronomic therapeutic combinations to enhance cytotoxicity and avoid resistance. Indeed, we found that the anti-apoptotic proteins BCL-xL and MCL-1 are crucial for ER+ breast cancer cells resistance to therapy, as they exert a dual inhibition of the pro-apoptotic protein BIM and compensate for each other. In addition, we identified the AKT inhibitor ipatasertib and two BH3 mimetics targeting these anti-apoptotic proteins, S63845 and A-1331852, as new potential therapies for this type of cancer. Therefore, we postulate the sequential inhibition of both proteins using BH3 mimetics as a new treatment option for refractory and relapsed ER+ breast cancer tumors.

    Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; bcl-X Protein; Breast Neoplasms; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Synergism; Estrogen Receptor alpha; Everolimus; Female; Fulvestrant; Gene Expression Regulation, Neoplastic; Humans; MCF-7 Cells; Myeloid Cell Leukemia Sequence 1 Protein; Piperazines; Protein Isoforms; Proto-Oncogene Proteins c-akt; Pyridines; Pyrimidines; Signal Transduction; Sulfonamides; Thiazoles; Thiophenes

2021