Ligand-Dependent Platelet-Derived Growth Factor Receptor (PDGFR)-α Activation Sensitizes Rare Lung Cancer and Sarcoma Cells to PDGFR Kinase Inhibitors

Abstract

Platelet-derived growth factor (PDGF) receptors (PDGFR) and their ligands play critical roles in several human malignancies. Sunitinib is a clinically approved multitargeted tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor, c-KIT, and PDGFR, and has shown clinical activity in various solid tumors. Activation of PDGFR signaling has been described in gastrointestinal stromal tumors (PDGFRA mutations) as well as in chronic myeloid leukemia (BCR-PDGFRA translocation), and sunitinib can yield clinical benefit in both settings. However, the discovery of PDGFR activating mutations or gene rearrangements in other tumor types could reveal additional patient populations who might benefit from treatment with anti-PDGFR therapies, such as sunitinib. Using a high-throughput cancer cell line screening platform, we found that only 2 of 637 tested human tumor-derived cell lines show significant sensitivity to singleagent sunitinib exposure. These two cell lines [a non-smallcell lung cancer (NSCLC) and a rhabdomyosarcoma] showed expression of highly phosphorylated PDGFRA. In the sunitinib-sensitive adenosquamous NSCLC cell line, PDGFRA expression was associated with focal PFGRA gene amplification, which was similarly detected in a small fraction of squamous cell NSCLC primary tumor specimens. Moreover, in this NSCLC cell line, focal amplification of the gene encoding the PDGFR ligand PDGFC was also detected, and silencing PDGFRA or PDGFC expression by RNA interference inhibited proliferation. A similar codependency on PDGFRA and PDGFC was observed in the sunitinib-sensitive rhabdomyosarcoma cell line. These findings suggest that, in addition to gastrointestinal stromal tumors, rare tumors that show PDGFC-mediated PDGFRA activation may also be clinically responsive to pharmacologic PDGFRA or PDGFC inhibition.

Olaratumab Exerts Antitumor Activity in Preclinical Models of Pediatric Bone and Soft Tissue Tumors through Inhibition of Platelet-Derived Growth Factor Receptor α

“…In addition, PDGFRa-activating ligands (namely, PDGFA and/or PDGFC) were also expressed in these cells lines. Conversely, PDGFRa was not expressed at the gene or protein level in the majority of rhabdomyosarcoma cell lines and PDX models in our study nor in a previous study that examined PDGFRa in SJCRH30 and other rhabdomyosarcoma cell lines (41). These findings were particularly surprising, as PDGFRa is readily detectable in rhabdomyosarcoma clinical specimens by qPCR or IHC and PDGFRA is a transcriptional target of the fusion protein driving alveolar rhabdomyosarcoma (PAX3-FOXO; refs.…”

SNAILs promote G1 phase in selected cancer cells

“…In order to maximally avoid the interference caused by genomic mutation (genomic instability), H292 cell line was used to establish stable cell lines. In the known non-small cell lung cancer cell lines, we found only H292 cells possess the relatively stable genome (with wild-type KRAS/TP53/EGFR/ERCC1/Keap1/ Nrf2) (28)(29)(30)(31)(32)(33)(34)(35)(36).…”

Pharmacokinetics and systems pharmacology of monoclonal antibody olaratumab for inoperable soft tissue sarcoma

“…McDermott et al [64,65] Human cancer cell lines of epidermoid carcinoma (A431), melanoma (A375), colon (Colo205), NSCLC (H460), glioma (SF763T and SF767T), breast (MDA-BM-435) Figure 2. Mechanism of action of olaratumab.…”