Background: Oncogenic KRAS is present in almost all cases of pancreatic ductal adenocarcinoma (PDAC). The mitogen-activated protein kinase (MAPK) pathway is the most cardinal signaling cascade utilized by KRAS, but targeting RAF or MEK, the key signaling nodes within this pathway has been clincally unsuccesful, largely due to ERK reactivation. Targeting ERK kinases has recently emerged as a promising therapeutic strategy, with several ERK inhibitor combinations now ongoing in clinical trials. However, resistance to ERK inhibitionn is inevitable and should be investigated.

Aim: Identify adaptive mechanisms that can be targeted to potentiate ERK inhibitors in PDAC to facilitate development of novel therapeutic combinations.

Methods: Reverse-phase protein array (RPPA) was used in early-passage patient-derived cell lines (PDCLs) to identify potential resistance mechanisms. These were confirmed using RNA interference and overexpression in PDAC cell lines and PDCLs. The promising combinations were tested in heterotypic spheroid cultures and in 30 early-passaged PDAC patient-derived xenografts (PDXs).

Results: RPPA showed dramatic downregulation of DUSP4 and DUSP6 protein levels following MEK and ERK inhibition in PDAC cells, which coincided with phospho-activation of HER2 and HER3. Knockdown of DUSP6, but not DUSP4, was sufficient in activating HER2. Conversely, overexpression of DUSP6 curbed HER2 and ERK activation. Combined ERK inhibitor (ulixertinib) and bortezomib was able to prevent DUSP4 and DUSP6 downregulation in vitro but was ineffective in curbing in vivo tumor growth. On the other hand, ulixertinib plus PI3K or pan-HER inhibitor afatinib is effective in PDCLs in vivo. Addition of gemcitabine greatly augmented the therapeutic efficacy of these combinations and achieved prolonged tumor suppression in several PDX models.

Conclusions: Our study provided novel mechanisic insight on how PDAC cells evade MAPK inhibition via mustering HER2 signaling, as well as rational therapeutic combinations that can be readily tested in clinical trials.

Keys: DUSP6, HER2, KRAS, pancreatic ductal adenocarcinoma, therapeutic resistance

Citation Format: Ashenafi Shiferaw Bulle. Pancreatic cancer musters HER2 signaling through DUSP6 to circumvent therapeutic MAPK inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1086.