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BACKGROUND Significant disparities in surgical outcomes exist. It is imperative to prepare future doctors to eliminate disparities. Our team of senior medical students developed a surgical clerkship module examining equity in prostate cancer. Student attitudes before and after a facilitated teaching session were assessed. METHODS A surgical equity pilot module was integrated into the core surgical clerkship starting in July 2020. This module was composed of (1) asynchronous preparatory material and (2) a synchronous interactive case discussion regarding disparities in prostate cancer. Discussion sessions were facilitated by upper-level medical students. Participants answered optional anonymous Likert-style and open-ended survey questions before and after the session. Pre- and post-responses were compared. RESULTS One hundred and sixteen students completed the module between July 2020 and January 2021. Pre- and post-survey response rates were 66% and 29%, respectively. At baseline, almost all students (95%) agreed knowledge of disparities would make them a better physician. However, the majority (95%) described their general knowledge of surgical disparities as "nonexistent," "poor," or "average." Most students did not have a framework for assessing causes of surgical disparities (86%) and were not aware of interventions for reducing disparities (90%). After intervention, the majority rated their knowledge of surgical disparities as "good" or "excellent" (71%; P < .001). Most students indicated they had a framework 79%; P < .001) and were aware of effective interventions (62%; P < .001). CONCLUSION We demonstrated a successful pilot of an equity-focused clerkship module. Student attitudes after a single session reflected significant improvement in knowledge of causes and interventions related to surgical disparities. Equity-focused teaching can be incorporated into the surgical clerkship.

Supplementary Figure S1. CONSORT diagram. Supplementary Figure S2. Histologic analysis of the pre-rociletinib biopsy from patient 12 (H&E 400x, left panel) demonstrates characteristic adenocarcinoma with an open chromatin pattern, ample cytoplasm and variable cell density. Supplementary Figure S3. Panel A. The nucleotide sequences of single-cell cloning analysis for six additional clones isolated from the afatinib-resistant cell line MGH176 are shown (see also figure 2B). Panel B. Summary of single-clone analyses performed on two additional patient-derived cell lines. Supplementary Figure S4. Longitudinal quantitative analyses of EGFR mutations in the ctDNA are shown for patients 8 (panel A), 6 (panel B) and 3 (panel C). Supplementary Figure S5. Scatterplot showing the relationship between the allelic fraction of T790M (calculated as the percent of T790M alleles/percent of EGFR activating mutation alleles as quantified by allele-specific PCR or NGS) in the pre-rociletinib tumor biopsy (y-axis) and in the pre-rociletinib plasma (as quantified by BEAMing) (x-axis).

Supplementary Figure Legends. Supplementary Table S1. Patient characteristics. Supplementary Table S2. Tissue genotyping analyses. Supplementary Table S3. Allelic Fraction of T790M and maximum reduction in tumor volume in response to rociletinib.

Top 10 correlated genes to BIM (BCL2L11)

Supplementary Figure 1 Legend. Describing the qPCR assay and variant allele frequency data that are included in the figure.

Supplemental legend

Purpose: A secondary EGFR mutation, T790M, is the most common resistance mechanism in EGFR-mutant adenocarcinomas that have progressed on erlotinib. Third-generation EGFR inhibitors capable of inhibiting mutant EGFR with T790M produce responses in nearly two thirds of patients. However, acquired resistance mechanisms in patients treated with these drugs are yet to be described.Experimental Design: To study acquired resistance to third-generation EGFR inhibitors, T790M-positive cells derived from an erlotinib-resistant cancer were made resistant to a third-generation TKI and then characterized using cell and molecular analyses.Results: Cells resistant to a third-generation TKI acquired an additional EGFR mutation, C797S, which prevented suppression of EGFR. Our results demonstrate that the allelic context in which C797S was acquired may predict responsiveness to alternative treatments. If the C797S and T790M mutations are in trans, cells will be resistant to third-generation EGFR TKIs, but will be sensitive to a combination of first- and third-generation TKIs. If the mutations are in cis, no EGFR TKIs alone or in combination can suppress activity. If C797S develops in cells wild-type for T790 (when third-generation TKIs are administered in the first-line setting), the cells are resistant to third-generation TKIs, but retain sensitivity to first-generation TKIs.Conclusions: Mutation of C797S in EGFR is a novel mechanism of acquired resistance to third-generation TKIs. The context in which the C797S develops with respect to the other EGFR alleles affects the efficacy of subsequent treatments. Clin Cancer Res; 21(17); 3924–33. ©2015 AACR.See related commentary by Ayeni et al., p. 3818

ZEB1 binding sites found in 1975R2 cells compared to 1975 parental cells

Purpose: Epithelial-to-mesenchymal transition (EMT) confers resistance to a number of targeted therapies and chemotherapies. However, it has been unclear why EMT promotes resistance, thereby impairing progress to overcome it.Experimental Design: We have developed several models of EMT-mediated resistance to EGFR inhibitors (EGFRi) in EGFR-mutant lung cancers to evaluate a novel mechanism of EMT-mediated resistance.Results: We observed that mesenchymal EGFR-mutant lung cancers are resistant to EGFRi-induced apoptosis via insufficient expression of BIM, preventing cell death despite potent suppression of oncogenic signaling following EGFRi treatment. Mechanistically, we observed that the EMT transcription factor ZEB1 inhibits BIM expression by binding directly to the BIM promoter and repressing transcription. Derepression of BIM expression by depletion of ZEB1 or treatment with the BH3 mimetic ABT-263 to enhance “free” cellular BIM levels both led to resensitization of mesenchymal EGFR-mutant cancers to EGFRi. This relationship between EMT and loss of BIM is not restricted to EGFR-mutant lung cancers, as it was also observed in KRAS-mutant lung cancers and large datasets, including different cancer subtypes.Conclusions: Altogether, these data reveal a novel mechanistic link between EMT and resistance to lung cancer targeted therapies. Clin Cancer Res; 24(1); 197–208. ©2017 AACR.

Supplementary Figure 1. EGFR amplification status and variant allele frequencies of T790M and C797S mutations for MGH121 parental and MGH121 resistant #1 cells.