MS31.03 Targeting the Hippo Pathway

Abstract

The prognosis for malignant pleural mesothelioma (MPM) remains poor and many anticipated advances in MPM treatment have been disappointing. One reason for the failure of conventional cytotoxic drugs is that they do not address the cancer stem cell population or the stem cell pathways that drive tumor resistance and resurgence following treatment. Cancer stem cells are defined by their properties of self-renewal, pluripotency, a high proliferative capacity and the ability to resist standard chemotherapy and radiation. Among the stem cell pathways, Hippo has proven to be critical to driving growth in MPM with mutations along this pathway implicated in the majority of MPM tumors. The Hippo pathway is a highly conserved regulator of organ size by regulating contact inhibition and of stem cell proliferation and maintenance.(1) The largest and most comprehensive genomic analysis to date of transcriptomes, whole exomes and targeted exomes from 216 MPM samples found Hippo pathway signaling to be the number one most significantly mutated pathway in mesothelioma with a Q-value of 1.70E-17, driven by mutations, copy number variations and fusions in NF2, LATS1, LATS2 and MST1.(2) One of the most frequently mutated genes in MPM is Neurofibromatosis type 2 (NF2) tumor suppressor, located at chromosome 22q12, and is detected in 40% to 50% of MPM tumors.(3) Large tumor suppressor homolog 2 (LAST2) gene, which is located at chromosome 13q12, is another frequently inactivated gene that is detected in 13% of MPM tumors. (3, 4) Inactivation of NF2 and LATS2 by deletion and/or mutation often contribute to dysregulation of Hippo pathway.(5) In addition to LATS2, its closest gene family member LATS1 another Hippo pathway gene, has also recently been identified to be dysregulated in MPM, though less commonly than LATS2. LATS1 is located on chromosome 6 and changes in copy number variation and fusions to Presenilin 1 (PSEN1) on chromosome 14 have been observed in MPM.(2, 3) Mammalian sterile-20 like kinase 1 (MST1) is an important upstream kinase in the Hippo pathway that has also been found to be dysregulated in MPM.(2) Given the high frequency of mutations and dysregulation in the Hippo pathway, it is a promising potential area of drug development. One specific target along the Hippo pathway is blocking Yes-associated protein (YAP) activity. In normal cells, Merlin, a protein encoded by NF2, and LATS2 contribute to the phosphorylation of the transcription factor YAP at S127,(6) resulting in YAP ubiquitination and activation of Hippo pathway to control cell proliferation. In MPM tumor cells, inactivation of NF2 and LATS2 prevent the phosphorylation of YAP at S127, which results in YAP relocation from the cytosol to nucleus where it interacts with TEA domain transcription factors (TEAD). In addition, constitutively activation of YAP has been identified in over 70% of primary MPM tumors, (3, 5, 7) and YAP activation leads to Hippo signaling attenuation and transcription of downstream target genes, such as connective tissue growth factor (CTGF) and Cyr61.(8) Low Merlin expression (NF2), results in YAP1 activation, and has been shown to be associated with worse clinical outcomes with shorter times to recurrence and shorter overall survival times in patients with MPM.(9) Blocking YAP activity, either via upstream inhibition of one of the several pathways that regulate YAP and Hippo or via direct YAP/TEAD inhibition is an area of active interest.(10) inhibitors are in preclinical development with promising results and may enter clinical trials in the near future.