# Project 3: Combination inhibition of ERK for pancreatic cancer treatment

> **NIH NIH P50** · WASHINGTON UNIVERSITY · 2020 · $212,596

## Abstract

PROJECT SUMMARY
The KRAS oncogene is mutated in ~95% of pancreatic ductal adenocarcinoma (PDAC). There is considerable
experimental evidence that continued expression of mutant KRAS is essential for PDAC maintenance. It is
generally accepted that an effective anti-KRas therapy will have a significant impact on pancreatic cancer, with
inhibition of KRAS effector signaling considered the most promising direction for advancement to the clinic. In
particular, considerable effort and interest is now focused on inhibitors of the Raf-MEK-ERK mitogen-activated
protein kinase (MAPK) cascade. However, Raf and MEK inhibitors have shown limited to no efficacy in RAS-
mutant cancers, due primarily to cancer cell adaptation and ERK reactivation to overcome the inhibitor action.
These findings have prompted the development of ERK inhibitors, with four inhibitors recently entering clinical
evaluation. Among them, BVD-523, a small molecule that targets ERK1 and ERK2 in the sub-nanomolar range
is the leading compound entering oncology clinical trials (NCT01781429). In our revised proposal, we now
provide substantial preclinical and clinical analyses of BVD-523 that support the rationale and feasibility of our
studies. The innovation of our studies is our focus on a first-in-class direct inhibitor of ERK and applying
unbiased genetic and chemical library screens to identify combination therapies to overcome limitations for its
use for PDAC. We also address the concern raised in our previous submission regarding undefined clinical
studies. We propose four Specific Aims to advance the clinical development of BVD-523 for PDAC treatment.
We will: (1) clinically evaluate BVD-523 anti-tumor activity and biomarkers of response in patients with PDAC;
(2) identify molecular mechanisms for acquired resistance to BVD-523 in KRAS-mutant PDAC; (3) identify
combination inhibitor approaches that overcome de novo resistance and render BVD-523 treatment cytotoxic;
and (4) assess combination inhibitor strategies with BVD-523 for anti-tumor activity in state-of-the-art organoid
culture and mouse models of pancreatic cancer. Our goal is to identify combinations that overcome de novo
and acquired resistance, as well as cytostatic and transient responses and normal tissue toxicity, for future
clinical evaluation. When completed, our study will have identified predictive biomarkers for ERK treatment
response, allowing us to identify the most effective ERK combinations to be tested in clinical studies.

## Key facts

- **NIH application ID:** 9982235
- **Project number:** 5P50CA196510-05
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Andrea Wang-Gillam
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $212,596
- **Award type:** 5
- **Project period:** — → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9982235

## Citation

> US National Institutes of Health, RePORTER application 9982235, Project 3: Combination inhibition of ERK for pancreatic cancer treatment (5P50CA196510-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9982235. Licensed CC0.

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