# The role of Sin1 in Kras-driven cancer

> **NIH NIH K99** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $107,044

## Abstract

PROJECT SUMMARY
Mutations in KRAS are among the most frequent in cancer, particularly in certain poor prognosis subtypes
such as lung and pancreatic adenocarcinomas. Extensive evidence suggests that KRAS is a cancer driver and
most tumors remain addicted to this oncoprotein. Biochemically, KRAS acts as a molecular binary switch that
cycles between a GTP-bound active state and a GDP-bound inactive state and KRAS oncogenic mutations
favor the active conformation. In the active state, KRAS associates with protein effectors that propagate the
downstream signal and contribute to the malignant phenotype. In this proposal, I describe the discovery of Sin1
as a novel potential KRAS effector and hypothesize its role in contributing to the initiation of KRAS-driven
malignancies. Through this application, I plan a series of advanced biochemical and structural experiments
aimed at determining whether Sin1 acts as a canonical Ras effector. Given the essential role of Ras effectors
during tumorigenesis, this project will also study the effect of Sin1 depletion in animal models and organoid
cultures transformed by an activated form of KRAS. Previous studies have shown that Sin1 is an essential
component of the mTOR complex 2 (mTORC2), which regulates kinase phosphorylation, metabolism, and is
itself central to proliferative signaling in cancer, but the contribution of KRAS in this context has not been
established at the molecular level. Moreover, early studies in model organisms have shown that Sin1 is a
component of the stress mitogenic pathways by interacting with MEKK2 and JNK. This proposal will address
how Sin1 may act at the intersection of these two pathways and KRAS: I will determine, through the use of
specific Sin1 separation-of-function mutants, whether the mechanisms of this potential KRAS effector are
mTORC2-dependent or independent. If successful, the results of this project will have a significant impact in
the field of KRAS signaling in particular and the cancer biology in general: the characterization of a novel
KRAS-specific effector critical for tumorigenesis. The results of this study could provide a strong rationale for
novel therapeutic approaches targeting previously uncharacterized KRAS effectors, a potential boon for
patients with KRAS-driven malignancies.
As part of my career development, I have put together a specific plan that includes activities for my mentored
phase (K99) that are aimed at facilitating my transition to an independent principal investigator position (R00),
including: a) Discussion with supervisor and advisory panel; b) Experience from personally conducting the
research; c) Mentoring experience; d) Institutional developmental resources and coursework; and e) Online
learning resources and bibliography. These activities will also be complemented by a strong mentorship from
the cancer researchers Dr. Frank McCormick, who will advise on the biochemistry, and the members of my
advisory panel Dr. Allan Balmain, who will ad...

## Key facts

- **NIH application ID:** 10054528
- **Project number:** 1K99CA245122-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Pau Castel
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $107,044
- **Award type:** 1
- **Project period:** 2020-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10054528

## Citation

> US National Institutes of Health, RePORTER application 10054528, The role of Sin1 in Kras-driven cancer (1K99CA245122-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10054528. Licensed CC0.

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