Martin C. Whittle

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Kinase inhibitors have limited success in cancer treatment because tumors circumvent their action. Using a quantitative proteomics approach, we assessed kinome activity in response to MEK inhibition in triple-negative breast cancer (TNBC) cells and genetically engineered mice (GEMMs). MEK inhibition caused acute ERK activity loss, resulting in rapid c-Myc(More)
Protein kinases are arguably the most tractable candidates for development of new therapies to treat cancer. Deep sequencing of breast cancer cell lines indicates each express 375 or so kinases, representing nearly 75% of the kinome. A rich network both downstream and upstream from key oncogenic kinases includes both tyrosine and serine/threonine kinases,(More)
For the majority of patients with pancreas cancer, the high metastatic proclivity is life limiting. Some patients, however, present with and succumb to locally destructive disease. A molecular understanding of these distinct disease manifestations can critically inform patient management. Using genetically engineered mouse models, we show that heterozygous(More)
Targeting the dysregulated BRAF-MEK-ERK pathway in cancer has increasingly emerged in clinical trial design. Despite clinical responses in specific cancers using inhibitors targeting BRAF and MEK, resistance develops often involving nongenomic adaptive bypass mechanisms. Inhibition of MEK1/2 by trametinib in patients with triple-negative breast cancer(More)
Protein kinases play key roles in oncogenic signaling and are a major focus in the development of targeted cancer therapies. Imatinib, a BCR-Abl tyrosine kinase inhibitor, is a successful front-line treatment for chronic myelogenous leukemia (CML). However, resistance to imatinib may be acquired by BCR-Abl mutations or hyperactivation of Src family kinases(More)
The RUNX family transcription factors are critical regulators of development and frequently dysregulated in cancer. RUNX3, the least well characterized of the three family members, has been variously described as a tumor promoter or suppressor, sometimes with conflicting results and opinions in the same cancer and likely reflecting a complex role in(More)
Purpose: TP53 and the TGFβ pathway are major mediators of pancreatic cancer metastasis. The mechanisms by which they cause hematogenous metastasis have not been fully explored.Experimental Design:KPC (LSL-KRASG12D/+;LSL-Trp53R172H/+; Ptf1aCre/+) mice were generated, and the frequency and morphology of organ-specific hematogenous metastases compared with(More)
Purpose:Anticancer drugdevelopment is inefficient, but genetically engineeredmurinemodels (GEMM) andorthotopic, syngeneic transplants (OST)of cancermayoffer advantages to in vitro andxenograft systems. Experimental Design: We assessed the activity of 16 treatment regimens in a RAS-driven, Ink4a/Arfdeficient melanoma GEMM. In addition, we tested a subset of(More)
Recent advances in proteomics have facilitated the analysis of the kinome 'en masse'. What these studies have revealed is a surprisingly dynamic network of kinase responses to highly selective kinase inhibitors, thereby illustrating the complex biological responses to these small molecules. Moreover these studies have identified key transcription factors,(More)