Search

The transition from undergraduate medical education (UME) to graduate medical education (GME) constitutes a complex system with important implications for learner progression and patient safety. The transition is currently dysfunctional, requiring students and residency programs to spend significant time, money, and energy on the process. Applications and interviews continue to increase despite stable match rates. Although many in the medical community acknowledge the problems with the UME-GME transition and learners have called for prompt action to address these concerns, the underlying causes are complex and have defied easy fixes. This article describes the work of the Coalition for Physician Accountability's Undergraduate Medical Education to Graduate Medical Education Review Committee (UGRC) to apply a quality improvement approach and systems thinking to explore the underlying causes of dysfunction in the UME-GME transition. The UGRC performed a root cause analysis using the 5 whys and an Ishikawa (or fishbone) diagram to deeply explore problems in the UME-GME transition. The root causes of problems identified include culture, costs and limited resources, bias, systems, lack of standards, and lack of alignment. Using the principles of systems thinking (components, connections, and purpose), the UGRC considered interactions among the root causes and developed recommendations to improve the UME-GME transition. Several of the UGRC's recommendations stemming from this work are explained. Sustained monitoring will be necessary to ensure interventions move the process forward to better serve applicants, programs, and the public good.

Glioblastoma (GBM) is an aggressive primary brain tumor with poor survival and limited treatment options. However, it is an attractive candidate for precision therapeutic approaches due to the frequency of amplification and/or activating mutations in the epidermal growth factor receptor (EGFR) gene and the availability of several brain penetrant second- and third-generation EGFR tyrosine kinase inhibitors (TKI). We used comprehensive molecular profiling of a panel of genetically engineered mouse astrocyte models to examine whether mutational profiles, particularly EGFR and PTEN status, could be used to identify kinases upregulated in specific mutational backgrounds. Using RNA-seq and multiplex inhibitor bead/mass spectrometry (MIB-MS) to analyze the kinase transcriptomes and proteomes, respectively, we have identified several potential targets for combination therapy. Overexpression of wild type EGFR in immortalized, Cdkn2a-/- astrocytes resulted in mild rewiring of the GBM kinome. Only 5 kinases aside from EGFR itself were overexpressed on either the transcript or protein levels. One overexpressed kinase, Hck, has been shown to be involved in cell survival, proliferation, adhesion, and migration. In contrast, overexpression of EGFRvIII, a constitutively active, extracellular domain truncation mutant of EGFR, resulted in significant alteration of the GBM kinome – 81 kinases showed differential expression, with 27 upregulated. One potentially attractive target among these was Cdk6, a drug-targetable, prognostically significant cyclin-dependent kinase implicated in proliferation, migration, and invasion. Finally, overexpression of EGFRvIII in cells lacking Pten dysregulated 46 kinases, including 15 upregulated. One particularly interesting target in these cells was Ddr2, a tyrosine kinase involved in migration, invasion, and extracellular matrix remodeling. We conclude that Hck, Cdk6, and Ddr2 represent attractive targets for therapeutic intervention in their relevant genetic contexts. These findings also suggest that molecular diagnostics for EGFR and PTEN status may be useful in guiding development of rational, EGFR TKI-centric drug combinations.

Glioblastoma (GBM) is a devastating primary brain tumor with 5-year survival < 5%. CDKN2A deletion (~60%) and EGFR amplification (55–60%) mutations frequently co-occur in these tumors. EGFR is an attractive therapeutic target due to its mutational frequency and availability of multiple brain-penetrant tyrosine kinase inhibitors (TKI). Several EGFR TKI have failed clinically, due in part to acquired resistance. To mechanistically examine this type of resistance, we used genetically engineered mouse astrocytes harboring Cdkn2a deletion and EGFRvIII, a common (35%) activating mutation. Resistant cells were generated via chronic exposure to gefitinib or erlotinib, either in vitro or in vivo. Resistance to these first-generation EGFR TKI conferred cross resistance (up to 36-fold ΔIC50) to a panel of second- and third-generation TKI relative to sensitive parental lines. Moreover, integrated RNA sequencing (RNA-seq) and chemical proteomics (multiplexed inhibitor beads and mass spectrometry (MIB-MS)) showed that the kinase transcriptome and proteome were rewired in resistant cells: 113 of ~300 detected kinases were differentially expressed (p< 0.05). We then used these techniques to examine acute (≤ 48 h) kinome changes in both sensitive and resistant cells upon treatment with a CNS-penetrant, second-generation EGFR TKI, afatinib. Whereas exposure of treatment-naïve, sensitive cells to afatinib significantly rewired the kinome (120 differentially expressed kinases), the response of resistant cells to drug re-challenge was significantly blunted (13 differentially expressed kinases). A subset of expressed kinases (35 of 263) dynamically responded to afatinib in both sensitive and resistant cells. Overall, upregulated kinases include those implicated in the biology of gliomas (Bmx, Fgfr2) and of other cancers (Pdgfrb, Mapk3/4, Ddr1/2, Pdk2). These kinases thus represent putative druggable targets for dual inhibition therapy. Integrated kinome profiling using MIB-MS and RNA-seq in GBM models with defined mutational profiles provides a powerful framework to identify novel therapeutic targets that could significantly alter current treatment paradigms.