# APC + TP53 Combinatorial Mutations Emerging as Biomarkers to Predict EGFRI Sensitivity

> **NIH NIH R21** · UNIVERSITY OF SOUTH FLORIDA · 2022 · $171,233

## Abstract

PROJECT SUMMARY/ABSTRACT
Colorectal cancer (CRC) is a major cause of cancer deaths which is curable if detected early. Unfortunately,
many CRC tumors are diagnosed at more advanced stages where cure rates remain low with 20% five-year
survival. The epidermal growth factor receptor (EGFR) is a major FDA-approved therapeutic target in metastatic
CRC that may be underutilized. To date, it is still difficult to identify patients who may benefit from EGFRi therapy.
In fact, the only identified biomarkers for EGFRi therapy are mutations in downstream genes that activate the
RAS pathway (KRAS (40%), NRAS (5%), and possibly BRAF (10%)). Unfortunately, these biomarkers are
negative predictors that are only ~50% accurate in predicting non-responders. Thus, accurate prediction of
EGFRi sensitivity is still problematic. We have recently employed a novel hybrid approach using a predictive
cetuximab sensitivity (CTX-S) gene expression signature score in 468 CRC tumors with coincident global gene
expression and exome sequencing data to identify mutations beyond those in KRAS/BRAF/NRAS that might
predict EGFRi responders. We found that tumors harboring the combination of APC + TP53 mutations are
predicted to be the most sensitive to cetuximab (CTX). Whereas most CRC tumors (70%) have truncating
mutations in APC and mutations in TP53 are present in 50% of CRC tumors, co-mutation of both genes is present
in ~25% of CRC and heretofore has never been rigorously measured in clinical trials. Thus, we hypothesize co-
mutated APC + TP53 as a new composite biomarker to identify CTX sensitive tumors that would allow greater
response rates in WT RAS/RAF patients and potentially extend therapy to some mutant KRAS patients. To
understand and validate the full potential of this novel biomarker, here we seek to determine the cellular impact
of the APC and TP53 mutations that increase the tumor sensitivity to EGFR inhibition. Further, we seek to identify
additional early/intermediate biomarkers of response correlating with the presence of these mutations. Finally,
we will determine if these mutations alter the gene expression–based consensus molecular subtype (CMS).
Tumors with CMS2 are predicted to have greater sensitivity to EGFR inhibition and appear to strongly correlate
with APC + TP53 mutations in our human datasets. We seek to determine if mutations in APC + TP53 can
convert molecular subtypes CMS1,3,4 to CMS2, coincident with enhancing EGFRi sensitivity. This application
will provide the necessary pre-clinical validation of novel molecular biomarkers to best predict which CRC tumors
will be responsive to EGFRi, and to support subsequent future clinical validation that may lead to expanded
application of an under-used, FDA-approved targeted therapy.

## Key facts

- **NIH application ID:** 10610600
- **Project number:** 7R21CA255312-02
- **Recipient organization:** UNIVERSITY OF SOUTH FLORIDA
- **Principal Investigator:** TIMOTHY J YEATMAN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $171,233
- **Award type:** 7
- **Project period:** 2022-04-16 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10610600

## Citation

> US National Institutes of Health, RePORTER application 10610600, APC + TP53 Combinatorial Mutations Emerging as Biomarkers to Predict EGFRI Sensitivity (7R21CA255312-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10610600. Licensed CC0.

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