1655P - Nampt inhibitors re-sensitize MAP17 expressing pancreas tumors

Background

The overexpression of MAP17, a small non-glycosylated membrane protein, has been described in a wide variety of human carcinomas, correlating with worse prognosis and response to different therapies. Pancreatic cancer (PC) has been the seventh major cause of cancer-related deaths worldwide in 2020, associated to a high mortality with a life expectancy of ∼5% at 5 years. Its aggressiveness makes necessary to identify new targets/biomarkers of response. The aim of this study was to assess the prognostic and predictive value of MAP17 expression in PC.

Methods

We evaluated MAP17 expression by immunohistochemistry in a cohort of 97 paraffin-embedded tissue samples of patients. We overexpressed MAP17 in two PC cells lines and tumorigenesis was analyzed using different functional assays and measuring several stem cell markers. We performed IC50 assays with different drugs and correlated them with MAP17 expression. Finally, we explored the effect of some of those treatments in vivo.

Results

High expression of MAP17 was detected only in pancreatic tumor cells. Also, we found that the overexpression of MAP17 increased the tumorigenic and stemness properties of cells as PC cell lines with high levels of MAP17 grew faster, formed higher number of colonies, holoclones, tumorspheres and a higher proportion of CD133+ cells. We explored whether the response to different antitumoral agents could be dependent on MAP17 expression, detecting that MAP17-expressing PC cells showed better response to gemcitabine, 5-FU, cisplatin and osimertinib, as well as resistance to docetaxel, bortezomib and ixazomib. However, in tumor xenografts in vivo, MAP17 expression confers resistance to all treatments. Next, we detected that the levels of total NAD, an essential metabolite implicated in many cellular processes, were higher in cells that overexpress MAP17. Finally, we found that the use of different inhibitors of NAMPT, the limiting enzyme of the synthesis of NAD, re-sensitize pancreatic tumor xenografts to classic chemotherapy.

Conclusions

MAP17 could serve as a prognostic and predictive biomarker in PC. Moreover, our findings could open new options of coadjuvant to current therapy with cisplatin or gemcitabine in PC that may eventually improve patients' outcomes.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

AC lab was supported by grants from the Ministerio de Ciencia, Innovación y Universidades (MCIU) Plan Estatal de I+D+I 2018, a la Agencia Estatal de Investigación (AEI) y al Fondo Europeo de Desarrollo Regional (MCIU/AEI/FEDER, UE): RTI2018-097455-B-I00 and RTI2018-096735-B-I00 grant from AEI-MICIU/FEDER (RED2018-102723-T); from CIBER de Cáncer (CB16/12/00275), co-funded by FEDER from Regional Development European Funds (European Union); from Consejeria de Salud (PI-0397-2017) and Consejeria of Economía, Conocimiento, Empresas y Universidad of the Junta de Andalucia (P18-RT-2501). Especial thanks to the AECCFoundation for supporting this work. EMV-S was funded by a postdoctoral contract from Consejería de Transformacion Economica, Industria, Conocimiento, y Universidades of the Junta de Andalucia, Spain ( CTEICU/PAIDI 2020 , DOC_01655). JM-P was funded by a Rio Hortega contract from Instituto de Salud Carlos III (ISCIII, CM18/00219).

Disclosure

All authors have declared no conflicts of interest.