Tumor Vulnerabilities and Genetic Dependencies
Do cancer cells have Achilles’ heels? The answer may lie in a concept called synthetic lethality, a therapeutic opportunity that arises when a combination of deficiencies in the expression of two or more genes leads to cell death, whereas a deficiency in only one of these genes does not.  Using genetically characterized PDX models and glioma neurosphere lines our lab has embarked on synthetic lethal approaches to discover tumor vulnerabilities and genetic dependencies in GBMs harboring alterations of the PTEN tumor suppressor gene.
PTEN regulates glioblastoma oncogenesis through chromatin-associated complexes of DAXX and histone H3.3: The product of two negatives
GBMs undergo genetic lesions that affect the epigenomic machinery that controls histone modifications, DNA methylation and gene expression. One such target is the histone H3 variant, H3.3, which is incorporated into chromatin in a cell cycle independent manner and is associated with transcriptionally active and silent chromatin in somatic and embryonic cells.  Histone chaperones that are involved in the recruitment of H3.3 to chromatin are DAXX (death-domain associated protein), ATRX (alpha-thalassemia /mental retardation X-linked syndrome protein) and HIRA (histone cell cycle regulator).  We discovered a novel chromatin-associated function of the PTEN tumor suppressor that represses oncogene expression and tumor growth in patient-derived glioma xenografts, through association with the DAXX-H3.3 complex. Our data show that DAXX physically interacts with PTEN, and PTEN regulates H3.3 loading on chromatin by limiting DAXX interactions with this histone, and thereby controls expression of several tumor-promoting genes. Moreover, DAXX inhibition affects global H3.3 deposition and gene expression, specifically suppresses intracranial tumor growth and significantly improves the survival of PTEN-null glioma-bearing mice. These results demonstrate a synthetic growth defect that occurs due to loss of these two tumor suppressor genes.
PTEN Y240 Phosphorylation promotes DNA Damage Repair and Tumor Cell Survival: When a tumor suppressor acts like an oncogene
Ionizing radiation (IR) and chemotherapy are standard of care treatments for GBM patients and both result in DNA damage, however, the clinical efficacy is limited due to therapeutic resistance. We identified a mechanism of such resistance mediated by phosphorylation of PTEN on tyrosine 240 (pY240-PTEN) by FGFR2. pY240-PTEN is rapidly elevated and bound to chromatin through interaction with Ki-67 in response to IR treatment and facilitates the recruitment of RAD51 to promote DNA repair. Blocking Y240 phosphorylation confers radiation sensitivity to tumors and extends survival in GBM preclinical models. Furthermore, Y240F-Ptenknock-in mice showed radiation sensitivity. These results suggest that FGFR-mediated pY240-PTEN is a key mechanism of radiation resistance and is an actionable target for improving radiotherapy efficacy.