To identify a novel amplified cancer gene a systematic screen of 975 human cancer DNA samples, 750 cell lines and 225 primary tumors, using the Affymetrix 10K SNP microarray was undertaken. The screen identified 193 amplicons. A previously uncharacterized amplicon located on 6p21.2 whose 1 Mb minimal common amplified region contained eight genes (GLO1, DNAH8, GLP1R, C6orf64, KCNK5, KCNK17, KCNK16, and C6orf102) was further investigated to determine which gene(s) are the biological targets of this amplicon. Real time quantitative PCR (qPCR) analysis of all amplicon 6p21.2 genes in 618 human cancer cell lines identified GLO1, encoding glyoxalase 1, to be the most frequently amplified gene [twofold or greater amplification in 8.4% (49/536) of cancers]. Also the association between amplification and overexpression was greatest for GLO1. RNAi knockdown of GLO1 had the greatest and most consistent impact on cell accumulation and apoptosis. Cell lines with GLO1 amplification were more sensitive to inhibition of GLO1 by bromobenzylglutathione cyclopentyl diester (BBGC). Subsequent qPCR of 520 primary tumor samples identified twofold and greater amplification of GLO1 in 8/37 (22%) of breast, 12/71 (17%) of sarcomas, 6/53 (11.3%) of nonsmall cell lung, 2/23 (8.7%) of bladder, 6/93 (6.5%) of renal and 5/83 (6%) of gastric cancers. Amplification of GLO1 was rare in colon cancer (1/35) and glioma (1/94). Collectively the results indicate that GLO1 is at least one of the targets of gene amplification on 6p21.2 and may represent a useful target for therapy in cancers with GLO1 amplification.

LKB1/STK11 is a multitasking tumour suppressor kinase. Germline inactivating mutations of the gene are responsible for the PeutzJeghers hereditary cancer syndrome. It is also somatically inactivated in approximately 30% of non-small-cell lung cancer (NSCLC). Here, we report that LKB1/KRAS mutant NSCLC cell lines are sensitive to the MEK inhibitor CI-1040 shown by a dose-dependent reduction in proliferation rate, whereas LKB1 and KRAS mutations alone do not confer similar sensitivity. We show that this subset of NSCLC is also sensitised to the mTOR inhibitor rapamycin. Importantly, the data suggest that LKB1/KRAS mutant NSCLCs are a genetically and functionally distinct subset and further suggest that this subset of lung cancers might afford an opportunity for exploitation of anti-MAPK/mTOR-targeted therapies.

New targeted approaches to ovarian clear cell carcinomas (OCCC) are needed, given the limited treatment options in this disease and the poor response to standard chemotherapy. Using a series of high-throughput cell-based drug screens in OCCC tumor cell models, we have identified a synthetic lethal (SL) interaction between the kinase inhibitor dasatinib and a key driver in OCCC, ARID1A mutation. Imposing ARID1A deficiency upon a variety of human or mouse cells induced dasatinib sensitivity, both in vitro and in vivo, suggesting that this is a robust synthetic lethal interaction. The sensitivity of ARID1A-deficient cells to dasatinib was associated with G 1 -S cell-cycle arrest and was dependent upon both p21 and Rb. Using focused siRNA screens and kinase profiling, we showed that ARID1A-mutant OCCC tumor cells are addicted to the dasatinib target YES1. This suggests that dasatinib merits investigation for the treatment of patients with ARID1A-mutant OCCC.

Introduction Professional identity development is a central aim of medical education, which has been disrupted during COVID-19. Yet, no research has qualitatively explored COVID-19’s impact across institutions or countries on medical students’ identities. Kegan proposes a cognitive model of identity development, where ‘disorientating dilemmas’ prompt student development. Given the potential of COVID-related disruption to generate disorientating dilemmas, the authors investigated the ways in which COVID-19 influenced students’ identity development. Methods The authors conducted an international qualitative study with second year medical students from Imperial College London, and third year students from Melbourne Medical School. Six focus groups occurred 2020–2021, with three to six students per group. Authors analysed data using reflexive thematic analysis, applying Kegan’s model as a sensitising theoretical lens. Results COVID-19 has resulted in a loss of clinical exposure, loss of professional relationships, and a shift in public perception of physicians. Loss of exposure to clinical practice removed the external validation from patients and seniors many students depended on for identity development. Students’ experiences encouraged them to assume the responsibilities of the profession and the communities they served, in the face of conflicting demands and risk. Acknowledging and actioning this responsibility facilitated identity development as a socially responsible advocate. Conclusions Educators should consider adapting medical education to support students through Kegan’s stages of development. Measures to foster relationships between students, patients, and staff are likely necessary. Formal curricula provisions, such as spaces for reflection and opportunities for social responsibility, may aid students in resolving the conflict many have recently experienced.

<p>Additional compounds included in the isogenic high-throughput drug screen</p>