Squamous Cell Carcinomas (SCC)
Although many of the pathways and targeted agents described thus far apply primarily to adenocarcinoma, targeted therapy for SCC is now a focus of current research. Recent discoveries from the cancer genome atlas about the molecular pathology of SCC have identified several important signalling pathways. Although these pathways can be inhibited, clinically meaningful benefits are currently lacking but ongoing work should hopefully see the realisation of targeted agents for SCC in the near future.
The phosphatidylinositol 3-kinase (PIK3CA) pathway is one of the most commonly altered in SCC with PIK3CA mutation and amplification as well as loss of the PTEN tumour suppressor gene. Ongoing phase II trials of the PI3K inhibitor, buparlisib (BKM120) are underway in squamous NSCLC in combination with chemotherapy (ClinicalTrials.gov Identifiers: NCT01911325, NCT01820325).
The fibroblast growth factor receptor 1 (FGFR1) is another exploitable pathway with overexpression in up to 20% of SCC compared to only 3% of adenocarcinoma. FGFR inhibitors, such as brivanib (BMS-582664) and other multi-kinase inhibitors showed positive signals in vitro and are now in early phase trials (ClinicalTrials.gov Identifier: NCT00633789).
DDR2 (discoidin domain receptor 2) is a tyrosine kinase receptor seen in up to 4% of SCC. Again DDR2, with collagen as its ligand, is involved in cell migration, proliferation and survival. Early promise was seen in vitro and in murine models of DDR2 inhibition with dasatinib, a multi-TKI targeting BCR-Abl and the Src family of tyrosine kinases. The phase II trial was negative but further research on DDR2 inhibition is ongoing.