Therapeutic targeting of TEAD transcription factors in cancer.

The Hippo signaling pathway inhibits the activity of the oncogenic YAP (Yes-associated protein)/TAZ (transcriptional co-activator with PDZ-binding motif)-TEAD (TEA/ATTS domain) transcriptional complex. In cancers, inactivating mutations in upstream Hippo components and/or enhanced activity of YAP/TAZ and TEAD have been observed. The activity of this transcriptional complex can be effectively inhibited by targeting the TEAD family of transcription factors. The development of TEAD inhibitors has been driven by the discovery that TEAD has druggable hydrophobic pockets, and is currently at the clinical development stage. Three small molecule TEAD inhibitors are currently being tested in Phase I clinical trials. In this review, we highlight the role of TEADs in cancer, discuss various avenues through which TEAD activity can be inhibited, and outline the opportunities for the administration of TEAD inhibitors.

Correction: Complementary activity of tyrosine kinase inhibitors against secondary kit mutations in imatinib-resistant gastrointestinal stromal tumours.

The additional information of this manuscript originally stated that the authors declare no competing interests. This statement was incorrect, and should instead have stated the following:M.C.H. has the following competing interests to declare: Equity interest at Molecular MD; Consulting at Molecular MD, Blueprint Medicines, Deciphera Pharmaceuticals; Expert Testimony at Novartis; Licensed patent with royalty payments at Novartis. The remaining authors have no competing interests to declare.The authors apologise for any convenience this may have caused.

Complementary activity of tyrosine kinase inhibitors against secondary kit mutations in imatinib-resistant gastrointestinal stromal tumours.

BACKGROUND: Most patients with KIT-mutant gastrointestinal stromal tumours (GISTs) benefit from imatinib, but treatment resistance results from outgrowth of heterogeneous subclones with KIT secondary mutations. Once resistance emerges, targeting KIT with tyrosine kinase inhibitors (TKIs) sunitinib and regorafenib provides clinical benefit, albeit of limited duration. METHODS: We systematically explored GIST resistance mechanisms to KIT-inhibitor TKIs that are either approved or under investigation in clinical trials: the studies draw upon GIST models and clinical trial correlative science. We subsequently modelled in vitro a rapid TKI alternation approach against subclonal heterogeneity. RESULTS: Each of the KIT-inhibitor TKIs targets effectively only a subset of KIT secondary mutations in GIST. Regorafenib and sunitinib have complementary activity in that regorafenib primarily inhibits imatinib-resistance mutations in the activation loop, whereas sunitinib inhibits imatinib-resistance mutations in the ATP-binding pocket. We find that rapid alternation of sunitinib and regorafenib suppresses growth of polyclonal imatinib-resistant GIST more effectively than either agent as monotherapy. CONCLUSIONS: Our data highlight that heterogeneity of KIT secondary mutations is the main mechanism of tumour progression to KIT inhibitors in imatinib-resistant GIST patients. Therapeutic combinations of TKIs with complementary activity against resistant mutations may be useful to suppress growth of polyclonal imatinib-resistance in GIST.

Broad Spectrum Activity of the Checkpoint Kinase 1 Inhibitor Prexasertib as a Single Agent or Chemopotentiator Across a Range of Preclinical Pediatric Tumor Models.

PURPOSE: Checkpoint kinase 1 (CHK1) inhibitors potentiate the DNA-damaging effects of cytotoxic therapies and/or promote elevated levels of replication stress, leading to tumor cell death. Prexasertib (LY2606368) is a CHK1 small-molecule inhibitor under clinical evaluation in multiple adult and pediatric cancers. In this study, prexasertib was tested in a large panel of preclinical models of pediatric solid malignancies alone or in combination with chemotherapy. EXPERIMENTAL DESIGN: DNA damage and changes in cell signaling following in vitro prexasertib treatment in pediatric sarcoma cell lines were analyzed by Western blot and high content imaging. Antitumor activity of prexasertib as a single agent or in combination with different chemotherapies was explored in cell line-derived (CDX) and patient-derived xenograft (PDX) mouse models representing nine different pediatric cancer histologies. RESULTS: Pediatric sarcoma cell lines were highly sensitive to prexasertib treatment in vitro, resulting in activation of the DNA damage response. Two PDX models of desmoplastic small round cell tumor and one malignant rhabdoid tumor CDX model responded to prexasertib with complete regression. Prexasertib monotherapy also elicited robust responses in mouse models of rhabdomyosarcoma. Concurrent administration with chemotherapy was sufficient to overcome innate resistance or prevent acquired resistance to prexasertib in preclinical models of neuroblastoma, osteosarcoma, and Ewing sarcoma, or alveolar rhabdomyosarcoma, respectively. CONCLUSIONS: Prexasertib has significant antitumor effects as a monotherapy or in combination with chemotherapy in multiple preclinical models of pediatric cancer. These findings support further investigation of prexasertib in pediatric malignancies.

Inactivation of Patched1 in mice leads to development of gastrointestinal stromal-like tumors that express Pdgfrα but not kit.

BACKGROUND & AIMS: A fraction of gastrointestinal stromal tumor (GIST) cells overexpress the platelet-derived growth factor receptor (PDGFR)A, although most overexpress KIT. It is not known if this is because these receptor tyrosine kinases have complementary oncogenic potential, or because of heterogeneity in the cellular origin of GIST. Little also is known about why Hedgehog (HH) signaling is activated in some GIST. HH binds to and inactivates the receptor protein patched homolog (PTCH). METHODS: Ptch was conditionally inactivated in mice (to achieve constitutive HH signaling) using a Cre recombinase regulated by the lysozyme M promoter. Cre-expressing cells were traced using R26R-LacZ reporter mice. Tumors were characterized by in situ hybridization, immunohistochemistry, immunoblot, and quantitative reverse-transcriptase polymerase chain reaction analyses. Cell transformation was assessed by soft agar assay. RESULTS: Loss of Ptch from lysozyme M-expressing cells resulted in the development of tumors of GIST-like localization and histology; these were reduced when mice were given imatinib, a drug that targets KIT and PDGFRA. The Hh signaling pathway was activated in the tumor cells, and Pdgfrα, but not Kit, was overexpressed and activated. Lineage tracing revealed that Cre-expressing intestinal cells were Kit-negative. These cells sometimes expressed Pdgfrα and were located near Kit-positive interstitial cells of Cajal. In contrast to KIT, activation of PDGFRA increased anchorage-independent proliferation and was required for tumor formation in mice by cells with activated HH signaling. CONCLUSIONS: Inactivation of Ptch in mice leads to formation of GIST-like tumors that express Pdgfrα, but not Kit. Activation of Pdgfrα signaling appears to facilitate tumorigenesis.

Immune competency of a hairless mouse strain for improved preclinical studies in genetically engineered mice.

Genetically engineered mouse models (GEMM) of cancer are of increasing value to preclinical therapeutics. Optical imaging is a cost-effective method of assessing deep-seated tumor growth in GEMMs whose tumors can be encoded to express luminescent or fluorescent reporters, although reporter signal attenuation would be improved if animals were fur-free. In this study, we sought to determine whether hereditable furlessness resulting from a hypomorphic mutation in the Hairless gene would or would not also affect immune competence. By assessing humoral and cellular immunity of the SKH1 mouse line bearing the hypomorphic Hairless mutation, we determined that blood counts, immunoglobulin levels, and CD4+ and CD8+ T cells were comparable between SKH1 and the C57Bl/6 strain. On examination of T-cell subsets, statistically significant differences in naïve T cells (1.7 versus 3.4 x 10(5) cells/spleen in SKH1 versus C57Bl/6, P = 0.008) and memory T cells (1.4 versus 0.13 x 10(6) cells/spleen in SKH1 versus C57Bl/6, P = 0.008) were detected. However, the numerical differences did not result in altered T-cell functional response to antigen rechallenge (keyhole limpet hemocyanin) in a lymph node cell in vitro proliferative assay. Furthermore, interbreeding the SKH1 mouse line to a rhabdomyosarcoma GEMM showed preserved antitumor responses of CD56+ natural killer cells and CD163+ macrophages, without any differences in tumor pathology. The fur-free GEMM was also especially amenable to multiplex optical imaging. Thus, SKH1 represents an immune competent, fur-free mouse strain that may be of use for interbreeding to other genetically engineered mouse models of cancer for improved preclinical studies.

Intravascular large B-cell lymphoma involving hemangiomas: an unusual presentation of a rare neoplasm.

We report the clinicopathological features of two cases of intravascular large B-cell lymphoma involving cutaneous hemangiomas. The cases were identified from the consultation files of two of the authors. Both patients were women, 64 and 55 years of age, who presented with long-standing cutaneous hemangiomas of the posterior scalp and left shoulder, respectively. The lesions were brought to medical attention by an increase in size and change in color. Biopsies and immunohistochemical evaluation of the hemangiomas revealed extensive involvement by intravascular large B-cell lymphoma. The neoplastic cells were diffusely positive for CD20 in both cases and negative for CD3, pan-cytokeratin (AE1/AE3), epithelial membrane antigen, S-100, Factor VIII-related antigen, CD34 and CD31. Disease was limited to the hemangiomas in both patients. Treatment consisted of chemotherapy (both patients) and adjuvant radiation therapy (one patient). One patient had a recurrence of disease 33 months after initial diagnosis, leading to an autologous stem cell transplant. The other patient is without evidence of disease 27 months after initial diagnosis. Although this is a rare neoplasm, it is important to consider intravascular large B-cell lymphoma in the differential diagnosis of vascular lesions containing intravascular neoplastic cells.