# Targeting the kinome in K-ras driven colorectal cancers

> **NIH NIH R01** · RESEARCH INST OF FOX CHASE CAN CTR · 2020 · $427,763

## Abstract

PROJECT SUMMARY/ABSTRACT
Mutations in RAS proteins, in particular K-ras, are common in human cancer, and the signaling pathways
emanating from this oncoprotein have been examined in detail. Despite intensive efforts to translate this
knowledge into improved cancer care, K-ras mutant tumors remain a formidable scientific and clinical challenge.
In this proposal, we focus on individual KRAS mutations that are commonly found in colorectal cancer (CRC),
because these mutations are associated with different sensitivities to targeted inhibitors and thus may engage
distinct signaling programs and require individualized therapeutic strategies. To access and exploit these distinct
programs, we employ an innovative mass spectrometry-based technique that enables the majority of the human
kinome to be analyzed simultaneously, providing the means to explore the K-ras induced kinome in an unbiased
fashion. Our unique approach combines mass spectrometry and protein kinase-capture beads to monitor
activated protein kinases from tumor cells, providing the ‘big picture’ of tumor kinase activity. Using this
technology, in Aim 1 we will measure the basal activity of the kinome in (i) a model isogenic CRC system that
represents common CRC associated KRAS mutant alleles and (ii) a panel of well characterized human KRAS
mutant CRC cell lines, before and after KRAS knockdown, to identify kinases whose activity is dependent on
expression of the various mutant forms of this oncogene. In Aim 2, we will explore the resiliency of the CRC
KRAS kinome(s) to MEK inhibition to identify and target compensatory kinases that promote resistance. In Aim
3, we will use this information to carry out a targeted synthetic lethal screen in vivo, testing the effectiveness of
inhibiting these activated protein kinases in KRAS dependent CRC xenografts and in CRC knock-in mouse
models driven by a common KRAS exon 2 (G12D) or an exon 4 (A146T) mutation. In this way, we hope to
identify individualized kinase inhibitor combinations that are effective in treating these common types of K-ras-
driven CRC.

## Key facts

- **NIH application ID:** 9828550
- **Project number:** 5R01CA211670-04
- **Recipient organization:** RESEARCH INST OF FOX CHASE CAN CTR
- **Principal Investigator:** James Stuart Duncan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $427,763
- **Award type:** 5
- **Project period:** 2016-12-08 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9828550

## Citation

> US National Institutes of Health, RePORTER application 9828550, Targeting the kinome in K-ras driven colorectal cancers (5R01CA211670-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9828550. Licensed CC0.

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