# Integrated genomic and proteomic profiling reveals insights into chemoradiation resistance in cervical cancer

## TL;DR

This study combines genomic and proteomic data to identify biomarkers and mechanisms of chemoradiation resistance in cervical cancer, offering new targets for treatment.

## Contribution

The first proteogenomic profiling of cervical cancer in the Indian population, linking molecular alterations to chemoradiation response.

## Key findings

- STK11 and STX3 are predictive biomarkers for poor chemoradiation response.
- EGFR is identified as a promising therapeutic target in resistant cervical cancer.
- An active DNA repair pathway is a critical mechanism of chemoradiation resistance.

## Abstract

Cervical cancer is highly prevalent in India, with most cases being diagnosed at advanced stages. Despite the standard concurrent chemoradiotherapy (CCRT), 30–40% of patients' experience treatment failure, underscoring the need for improved therapeutic strategies. Understanding resistance mechanisms and identifying predictive biomarkers are crucial to improve treatment efficacy and enable personalized medicine. We conducted a comprehensive genomic and proteomic analysis to identify molecular signatures associated with CCRT. We identified recurrent mutations in phosphatidylinositol 4,5‐bisphosphate 3‐kinase catalytic subunit alpha isoform (PIK3CA) and histone‐lysine N‐methyltransferase 2D (KMT2D), with mutation signature analysis revealing a prevalent DNA dC‐ > dU‐editing enzyme, APOBEC mutagenesis signature. Distinct genomic alterations, including epidermal growth factor receptor (EGFR) amplification and serine/threonine kinase 11 (STK11) deletion, were exclusively observed in the chemoradiation‐resistant cohort. Proteomic analysis identified 73 significantly dysregulated proteins, with syntaxin‐3 (STX3), SERPINB7, lipopolysaccharide‐binding protein (LBP), EMILIN2, and ribosyldihydronicotinamide dehydrogenase (quinone) (NQO2) being the top five upregulated proteins. Integrative pathway analysis highlighted an active DNA repair pathway in the resistant cohort. This study presents the first proteogenomic profiling of cervical cancer in the Indian population, linking molecular alterations to CCRT response. STK11 and STX3 emerged as predictive biomarkers for poor response, whereas EGFR presents as a promising therapeutic target in the resistant group.

A comprehensive genomic and proteomic analysis of cervical cancer revealed STK11 and STX3 as a potential biomarkers of chemoradiation resistance. Our study demonstrated EGFR as a therapeutic target, paving the way for precision strategies to overcome treatment failure and the DNA repair pathway as a critical mechanism of resistance.