# REGULATION AND ADAPTIVE MECHANISMS OF ONCOGENIC RAS/ERK SIGNALING

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $417,319

## Abstract

Project Summary/Abstract
Over 40% of human cancers are driven by hyperactivated RTK/RAS/RAF/MEK/ERK signaling (MAPK
pathway). Targeting MAPK signaling using small-molecule RAF or MEK inhibitors is a validated therapeutic
strategy in cancer, but the antitumor activity of these drugs is commonly attenuated by various mechanisms of
adaptive resistance. One such common mechanism is the result of relief of negative feedback which promotes
upregulation of expression and activity of multiple Receptor Tyrosine Kinases (RTKs), which in turn activate
RAS and downstream MAPK signaling in the presence of inhibitor. Further, questions relating with how MAPK-
directed therapies can achieve a higher therapeutic index by minimally affecting normal tissue and how can
they be optimally combined with immune checkpoint therapies remain largely unresolved. SHP2 (PTPN11) is a
non-receptor protein tyrosine phosphatase that mediates signal transduction downstream of multiple RTKs by
associating with GRB2 and other adaptor proteins to form a complex that promotes RAS activation. SHP2 has
also been suggested to have an immunosuppressive role, but this function of SHP2 has also been relatively
understudied. The recent development of potent and selective allosteric small-molecule inhibitors targeting
SHP2 provided the opportunity to potentially overcome adaptive resistance by co-targeting both oncogenic
signaling and feedback-induced RTK-mediated RAS activation in tumors dependent on deregulated MAPK
signaling. Using one such SHP2 inhibitor, SHP099, we found that combinatorial targeting of SHP2 and MAPK
signaling prevented adaptive resistance in defined subsets of MAPK-dependent tumors. In each MAPK-driven
tumor analyzed, induction of p(Y542)SHP2, a surrogate marker of SHP2 activation, in response to MAPK
inhibition was required for combined treatment sensitivity. The strategy was broadly effective in tumor models
representing aggressive cancer types for which there are no targeted therapeutic options currently available,
including Triple Negative Breast Cancer (TNBC) models, as well as tumors with RAS mutations at G12. In
contrast, RAS(G13D)/(Q61X) mutations were associated with tumor resistance to the combination, revealing a
hitherto unappreciated complexity of mutant-RAS signaling and variability in the dependence of different RAS
mutants on upstream RTK/SHP2 signaling. Finally, using an in vitro co-culture tumor cells/T cells system we
found that SHP2 inhibition enhances T cell function. Based on these observations, we now plan to use specific
inhibitors and biochemical and cell-based methods to comprehensively study mechanisms that regulate wild-
type and mutant RAS activity downstream of RTK/SHP2 signaling. We will further investigate ex vivo and in
vivo for molecular and tumor type-specific determinants of response to combined SHP2 and MAPK inhibition,
that may be used as potential biomarkers and of the effects of these therapies on normal tissue and the
immune syst...

## Key facts

- **NIH application ID:** 10160858
- **Project number:** 5R01CA240362-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Poulikos I Poulikakos
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $417,319
- **Award type:** 5
- **Project period:** 2020-05-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10160858

## Citation

> US National Institutes of Health, RePORTER application 10160858, REGULATION AND ADAPTIVE MECHANISMS OF ONCOGENIC RAS/ERK SIGNALING (5R01CA240362-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10160858. Licensed CC0.

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