Preclinical models of diffuse-type gastric cancer (DGC) that reliably predict clinical activity of novel compounds are lacking. To overcome the problem of poor tumor cellularity in DGC, we used cells from malignant ascites to establish DGC patientderived xenograft (PDX) models that recapitulate the primary cancer. Cells in PDX model GAGA6 with FGFR2 amplification were sensitive to AZD4547, a potent FGFR inhibitor that is being clinically evaluated for FGFR-aberrant cancer types. Intermittent in vivo treatment of GAGA6 tumors with AZD4547 gave rise to PDX tumors with acquired resistance to AZD4547, GAGA6-R. Surprisingly, there were no mutations in the FGFR2 gene in GAGA6-R, negating gatekeeper mutations as a mechanism of drug resistance. Phosphorylation of FGFR2 and downstream signaling molecules AKT/PKB and MAPK/ERK remained inhibited by AZD4547. Further analysis of signaling pathways identified AKT-independent phosphorylation and inhibition of GSK3b as a mechanism of drug resistance in GAGA6-R cells. Treatment of GAGA6-R cells with protein kinase C (PKC) inhibitor H7 in combination with AZD4547 led to dephosphorylation and activation of GSK3b with concomitant downregulation of MCL-1 and BCL-XL. Combined treatment with AZD4547 and H7 in vitro synergistically enhanced cell death in GAGA6-R but not GAGA6 cells. Furthermore, midostaurin, a multikinase inhibitor with PKC-inhibiting activity, in part reversed resistance of GAGA6-R tumor to AZD4547 in vivo. Our results suggest that upon challenge with FGFR inhibitors, FGFR2-amplified tumors that are highly dependent on FGFR2 signaling for survival rapidly develop resistance by switching to a PKC-mediated inhibition of GSK3b to gain a survival advantage.

Background Experiential learning through service provides opportunities to nurture and practice empathy. Of growing concern, studies showed significantly decreased empathy scores as students progress through medical school. Additionally, peer-to-peer learning provides an effective way for students to learn. Constructing Care Collaboration (CCC) is a student initiated, structured-service-learning-program that promotes the development of empathy and peer-to-peer teaching. CCC is conducted in cycles of 6 sessions. This is a mixed methods study that explores the effectiveness of CCC as a service learning platform in developing student participants’ empathy, social and cultural competencies, communication skills and peer-to-peer teaching skills, ultimately aiming to promote a culture of serving the underprivileged. Methods The study comprised of a self-administered quantitative questionnaire and qualitative interviews. Both evaluated if CCC participation developed volunteers’ social-awareness, cultural competency, communication, confidence and motivation to teach their peers. Results Quantitative data were collated from 38 completed student volunteers’ questionnaires. Volunteers generally agreed CCC improved social-awareness and cultural competency. It increased confidence of participants in approaching migrant-workers, communicating with people from different social backgrounds, and promoted a culture of peer-to-peer teaching. Thematic analysis of 17 interviews was conducted. Themes identified include: increased empathy towards migrant-workers, improved communication skills, and identifying benefits and challenges in peer-to-peer teaching. Conclusion From the quantitative and qualitative information gathered, CCC has been shown to be effective in nurturing participants’ self-reported empathy, cultural competence, communication skills and improved attitude towards peer-to-peer teaching. Given its effectiveness, CCC can be adopted as a model for structured service-learning. Electronic supplementary material The online version of this article (10.1186/s12909-019-1740-6) contains supplementary material, which is available to authorized users.

<p>Clinicopathological features of GAGA patients</p>

<p>Amplified chromosomal regions in GAGA samples</p>