Biomarkers

Tumor levels of PHLDA1 could help predict resistance to RTK inhibitors in endometrial, breast and other cancers. In tumor samples from patients with metastatic breast cancer or locally advanced non-metastatic renal cancer treated with various RTK inhibitors, low levels of PHLDA1 protein were associated with acquired drug resistance. Transcriptomic profiling of human endometrial cancer cell lines harboring activating mutations in keratinocyte growth factor receptor (KGFR; FGFR2; CD332) identified an association between low expression levels of PHDLA1 mRNA and resistance to inhibitors of fibroblast growth factor receptor (FGFR) or FGFR1 (CD331). In one of the corresponding wild-type cancer cell lines, shRNA targeting PHLDA1 decreased sensitivity to the FGFR inhibitor AZD4547 compared with a scrambled shRNA, and culturing for 14 days in 1 μM AZD4547 induced drug resistance comparable to that observed in PHLDA1-knockdown cells, as measured by proliferation rates. In two epidermal growth factor receptor 2 (HER2; EGFR2; ErbB2; neu)-positive breast cancer cell lines, induction of drug resistance with the HER1/HER2 inhibitor Tykerb lapatinib or the anti-HER2 antibody Herceptin trastuzumab decreased PHLDA1 protein levels compared with vehicle or an IgG control. In a xenograft mouse model of HER2-positive breast cancer, Herceptin decreased tumor levels of PHLDA1 mRNA compared with the control IgG. Next steps include using PHLDA1 expression to predict which patients would respond to drug therapies.

AstraZeneca plc has AZD4547 in Phase II testing to treat solid tumors...