# Studies on oncoprotein-induced feedback: Basic and therapeutic implications

> **NIH NIH R35** · SLOAN-KETTERING INST CAN RESEARCH · 2021 · $1,077,600

## Abstract

PROJECT SUMMARY / ABSTRACT
We have established that oncoproteins which function as dysregulated components of mitogenic
signaling pathways cause marked feedback inhibition of physiologic signaling. Much of our recent work
has focused on understanding the implications of this phenomenon. Insensitivity to feedback inhibition
of receptor activation of wild type RAS is a common property of oncoproteins that activated ERK
signaling that is required for them to elevate ERK output. Second, elevated pathway output includes
elevated feedback inhibition of physiologic signaling pathways. This is a major determinant of the so-
called oncoprotein dependence of transformed cells. Third, feedback-dependent oncoprotein pathway
dependence reduces the robustness of the cell and creates a selection for mutations that activate
feedback-Inhibited pathways and restores robustness. This accounts for some of the secondary driver
mutations identified in tumors. Finally, inhibitors of oncoprotein-activated signaling have significant
antitumor activity, but also relieve feedback inhibition of physiologic mitogenic signaling pathways and
cause their reactivation. This attenuates their antitumor activity and creates a logic for inhibiting key
reactivated pathways in tumors exposed to inhibitors of oncoproteins. This strategy has had some early
clinical success and has become a paradigm for the development of rational combination therapies.
Despite these insights, we still know only few of the details of oncoprotein-induced feedback and its
relief by targeted inhibitors. We do know that these details vary as a function of tumor lineage and
which pathway component is mutationally activated. Moreover, the effects of relieving feedback also
vary depending on which node of the pathway is pharmacologically inhibited. We now plan to
comprehensively study feedback and its relief by nodal inhibitors, focusing on a few tumors and using
both methodologies biased by previous knowledge of normal signaling and unbiased shRNA screens.
We utilize selective inhibitors of PI3K, AKT, mTOR, RAF, MEK, ERK, and a novel allele-specific
inhibitor of RAS and study both short- and long-term adaptation, to determine whether some of the
effects of the latter are due to epigenetic regulation. The goal is to develop new effective combination
therapies based on these data and on in vivo studies to determine dose schedules that optimize
induction of cell death.

## Key facts

- **NIH application ID:** 10247722
- **Project number:** 5R35CA210085-06
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** NEAL ROSEN
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,077,600
- **Award type:** 5
- **Project period:** 2016-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247722

## Citation

> US National Institutes of Health, RePORTER application 10247722, Studies on oncoprotein-induced feedback: Basic and therapeutic implications (5R35CA210085-06). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10247722. Licensed CC0.

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