Journal: Annals of Oncology

Article Title: What hides behind the MASC: clinical response and acquired resistance to entrectinib after ETV6-NTRK3 identification in a mammary analogue secretory carcinoma (MASC)

doi: 10.1093/annonc/mdw042

Figure Lengend Snippet: A durable partial response is achieved with entrectinib therapy in an ETV6-NTRK3 -rearranged mammary analogue secretory carcinoma. Computed tomography (CT) imaging of the patient after progression on crizotinib and before entrectinib therapy is shown on the left. Repeat CT imaging at 9 weeks revealed a dramatic partial response to therapy (RECIST v1.1) with an interval decrease and resolution of pleural-based metastases in the right hemithorax (arrows). This response was confirmed at 13 weeks and further shrinkage was noted at 21 weeks. A best radiologic response of 89% reduction in tumor burden from baseline was achieved.

Article Snippet: For the ETV6-NTRK3 fusion, entrectinib was more potent than other Trk inhibitors: TSR-011 (Tesaro), LOXO-101 (LOXO), and crizotinib (IC 50 values of 2 nM for entrectinib, 14 nM for LOXO-101, 59 nM for TSR-011, and 88 nM for crizotinib, supplementary Figures S4A and S4B, available at Annals of Oncology online ).

Techniques: Computed Tomography, Imaging

Journal: Annals of Oncology

Article Title: What hides behind the MASC: clinical response and acquired resistance to entrectinib after ETV6-NTRK3 identification in a mammary analogue secretory carcinoma (MASC)

doi: 10.1093/annonc/mdw042

Figure Lengend Snippet: The development of clinical entrectinib resistance is mediated by the appearance of a novel NTRK3 G623R mutation. In panel A, areas of tumor acquisition via serial biopsies are depicted: before crizotinib (M1, paraesophageal right lower lobe mass), after progression on crizotinib and before entrectinib (M2a, pleural-based right lower lobe mass), and after progression on entrectinib (M2b, pleural-based right lower lobe mass immediately adjacent to M2a). In panel B, broad, hybrid-capture-based next-generation sequencing confirmed the appearance of an NTRK3 G623R mutation after progression on entrectinib (M2b) that was not present in pre-entrectinib tumor samples (M1 and M2a). Panel C depicts the antiproliferative activity of entrectinib in engineered Ba/F3 cells expressing a variety of Trk fusion proteins with IC50s ranging from 1.4 to 4.5 nM. Entrectinib was found to inhibit phospho-TrkC and phospho-PLCy1, with less inhibition of PI3K, MAPK, and Stat3 as depicted in panel D. In panel E, introduction of the NTRK3 G623R mutation into the ETV6-NTRK3 construct (Ba/F3-ETV6-NTRK3 G623R) conferred reduced sensitivity to entrectinib, increasing the IC 50 value in the proliferation assays by more than 250-fold relative to the Ba/F3-ETV6-NTRK3 cells. Homology alignment in panel F suggests that the native glycine at position 623 of TrkC is highly conserved among TrkC paralogs. A comparison to glycine residues at position 1202 of ALK, position 2032 of ROS1, and position 595 of TrkA, in addition to other paralogs, is shown. Panel G depicts the binding of entrectinib to both wild-type TrkC and NTRK3 G623-mutant TrkC. Extensive hydrogen bonding and hydrophobic interactions between wild-type TrkC and entrectinib occur in the ATP binding pocket where the G623 residue is located (left). The substitution of arginine for glycine at position 623 results in steric hindrance that decreases the binding of entrectinib to mutant TrkC (right).

Article Snippet: For the ETV6-NTRK3 fusion, entrectinib was more potent than other Trk inhibitors: TSR-011 (Tesaro), LOXO-101 (LOXO), and crizotinib (IC 50 values of 2 nM for entrectinib, 14 nM for LOXO-101, 59 nM for TSR-011, and 88 nM for crizotinib, supplementary Figures S4A and S4B, available at Annals of Oncology online ).

Techniques: Mutagenesis, Next-Generation Sequencing, Activity Assay, Expressing, Inhibition, Construct, Comparison, Binding Assay, Residue