Deep Sequencing Uncovers Unique Aberrations
In another in-depth analysis of a metastatic bladder cancer patient with an exceptional response to everolimus, whole-genome sequencing identified a loss-of-function mutation in TSC1, a regulator of the mTOR pathway activation, as the basis of response. A second patient with a difficult-to-describe malignant neoplasm that defied conventional histologic and immunohistochemical characterization presented a diagnostic and therapeutic challenge. This patient, with an obscure sarcoma-like undifferentiated lesion that failed conventional chemotherapies, responded in a Phase I trial combining sorafenib, temsirolimus and bevazicumab. Clinical next-generation sequencing identified a KIAA1549–BRAF fusion and PTEN loss in this patient, identifying the basis of response to be a dual inhibition of RAF kinase and mTOR. This case was the first report of this sarcoma-type tumor driven by a KIAA1549–BRAF fusion responding to sorafenib-based combination therapy. In another exceptional responder study, whole-exome sequencing of a urothelial carcinoma patient with a complete response lasting 14 months in a Phase I trial of pazopanib and everolimus revealed two concurrent mutations in mTOR, the target of everolimus, namely an activating mutation (mTOR ) and a second mutation (mTOR ), which were also confirmed by preclinical validation studies. Even in aggressive malignancies, such as small-cell lung cancer, whole-genome sequencing of exceptional responders to combined CHK1 inhibition and DNA-damaging chemotherapy revealed a clonal hemizygous mutation in the Mre11 complex gene RAD50 that attenuated ataxia telangiectasia mutated-dependent signaling, which, in the context of CHK1 inhibition, contributed to the extreme sensitivity to irinotecan via synthetic lethality.