Project description:Oncogene addiction provides important therapeutic opportunities for precision oncology treatment strategies. To date the cellular circuitries associated with driving oncoproteins, which eventually establish the phenotypic manifestation of oncogene addiction remain largely unexplored. We employed a targeted mass spectrometry approach to systematically explore alterations in 116 phosphosites related to oncogene signaling and its intersection with the DDR following inhibition of the addicting oncogene alone or in combination with irradiation in MET-, EGFR-, ALK- or BRAF (V600)-positive cancer models and ex vivo non-small cell lung cancer patient organotypic cultures. We identified an ‘oncogene addiction phosphorylation signature’ (OAPS) consisting of 8 protein phosphorylations (ACLY S455, IF4B S422, IF4G1 S1231, LIMA1 S490, MYCN S62, NCBP1 S22, P3C2A S259 and TERF2 S365) that are significantly suppressed upon targeted oncogene inhibition solely in addicted cell line models and patient tissues. We show that the OAPS is present in patient tissues and the OAPS-derived score strongly correlates with the ex vivo responses to targeted treatments.
Project description:miR-17-92 mediates the MYC oncogene addiction in a conditional mouse lymphoma model. To identify targets of miR-17-92 in this model, miR-17-92 was expressed in the conditional lymphoma cell lines using MSCV-puro. Both control and miR-17-92-expressing conditional lymphoma cell lines were treated with doxycycline (DOX) (20ng/ml) for 48 hours to shut off MYC expression.
Project description:miR-17-92 mediates the MYC oncogene addiction in a conditional mouse lymphoma model. To identify targets of miR-17-92 in this model, miR-17-92 was expressed in the conditional lymphoma cell lines using MSCV-puro.
Project description:The suppression of oncogenic levels of MYC is sufficient to induce sustained tumor regression associated with proliferative arrest, differentiation, cellular senescence and/or apoptosis, a phenomenon known as oncogene addiction. However, after prolonged inactivation of MYC in a conditional transgenic mouse model of Em-tTA/tetO-MYC T-acute lymphomablastic lymphoma (T-ALL), some of the tumors recur, recapitulating what is frequently observed in human tumors in response to targeted therapies. Here we report that these recurring lymphomas express high levels of either transgenic or endogenous Myc suggesting that tumors continue to be addicted to oncogenic levels of MYC. Many of the recurring lymphomas (76%) harbored mutations in the tetracycline transactivator (tTA) resulting in expression of the MYC transgene even in the presence of doxycycline. Many of the remaining recurring tumors expressed high levels of endogenous Myc which was in some cases associated with a genomic rearrangement of the endogenous Myc locus or overexpression of Notch1. Gene expression profiling confirmed that the primary and recurring tumors have highly similar transcriptomes. Importantly, shRNA-mediated suppression of the high levels of MYC in recurring tumors elicited both suppression of proliferation and increased apoptosis confirming that these tumors remain oncogene addicted. These results suggest that tumors caused by MYC overexpression remain addicted to high levels of expression of this oncogene. 13 samples, no replicates included
