CIN Signatures Predict Chemotherapy Resistance
Researchers have harnessed CIN signatures to forecast chemotherapy resistance, opening doors to precision oncology.
Complete the form below to unlock access to ALL audio articles.
A new genomic test has been developed to accurately predict whether a patient’s cancer will resist common chemotherapy treatments.
Created by Scientists at the Cancer Research UK (CRUK) Cambridge Institute, the Spanish National Cancer Research Centre (CNIO) and Cambridge-based startup Tailor Bio, the test analyzes chromosomal instability (CIN) signatures – distinctive patterns in DNA structure, order and copy number changes – offering a more tailored approach to cancer therapy. A study analyzing the test’s performance is published in Nature Genetics.
Decoding chemotherapy resistance with CIN
Chemotherapy remains a cornerstone of cancer treatment, but its effectiveness varies significantly across patients and is often accompanied by severe and unpleasant side effects.
“Chemotherapy is a mainstay of cancer treatment and saves many lives. Yet in many cases, it has been administered the same way for over 40 years,” said Professor James Brenton from CRUK Cambridge Institute. “Sadly, there are too many cases where cancer is resistant to chemotherapy, meaning unpleasant side-effects for the patient with limited benefit to them.”
The new test capitalizes on advances in genomic sequencing to assess CIN – a form of genetic chaos found in many cancers.
What is chromosomal instability?
CIN signatures are detected by comparing the full DNA sequence of tumor cells to normal cells, identifying recurring patterns of DNA damage caused by defective cellular processes.
“Each type of CIN leaves a distinct pattern of DNA damage,” Dr. Geoff Macintyre, chief scientific officer at Tailor Bio and computational oncology group leader at the CNIO, told Technology Networks. “By identifying and quantifying these patterns, we can pinpoint the defective biology causing the damage and match it to therapeutic vulnerabilities. Some of these vulnerabilities can be targeted using existing therapies (e.g., chemotherapies or DNA damage response drugs), but we are also developing new therapies to explicitly target different types of CIN.”
This test can predict resistance to three commonly used chemotherapy types: platinum-based, anthracyclines and taxanes. According to Cancer Research UK and NHS England, tens of thousands of patients receive these treatments annually in England alone.
Turning chemotherapy into a precision medicine
Despite a well-understood mechanism of action for many chemotherapies, until now, there has been no accurate way to match treatments to the underlying biology of each tumor.
“Our technology is the first to properly decode CIN,” said Macintyre. “The CIN signature biomarkers unlock the ability to match tumors to chemotherapy mechanisms.”
The research team piloted the test on data from 840 patients with various cancers. Patients were classified as “chemotherapy resistant” or “chemotherapy sensitive” and virtually reassigned to different chemotherapy treatments. The simulation revealed that predicted resistance aligned with higher failure rates in multiple cancer types:
- Taxane resistance: higher failure in ovarian, metastatic breast and metastatic prostate cancer
- Anthracycline resistance: higher failure in ovarian and metastatic breast cancer
- Platinum resistance: higher failure in ovarian cancer.
“The technology is essentially turning chemotherapies into precision medicines,” said Macintyre. “As chemotherapies are some of the most effective treatments available, we expect they will perform as well as newer targeted therapies with the use of our biomarkers.”
The test is compatible with whole-genome sequencing (WGS), targeted panels and cell-free DNA. However, balancing performance with cost-effectiveness and scalability in clinical settings is something that still needs to be explored. Tailor Bio has also developed a cost-effective, low-pass WGS assay that works on formalin-fixed diagnostic samples without requiring additional biopsies. Though effective in over 80% of clinical samples, liquid biopsy applications currently succeed in only 30% of cases.
“We hope to work with existing assay providers to explore rapid adoption of our computational approach to predicting resistance,” Macintyre said.
Uncovering Hidden Genomic Variation in Rare and Complex Diseases
This webinar explores how the long, real-time reads delivered by Oxford Nanopore sequencing can resolve challenging genomic regions and detect base modifications in a single data set, providing access to previously hidden variation in rare and compleView Webinar
Tailored treatment for chemotherapy patients
Current chemotherapy strategies often apply a one-size-fits-all approach. This new test aims to change that by identifying patients unlikely to benefit from standard chemotherapy, sparing them from unnecessary toxicity and directing them toward more effective options.
“We tuned our test to identify those who are resistant,” said Dr. Ania Piskorz, co-lead author and head of genomics at CRUK Cambridge Institute. “We want to prevent them from suffering the debilitating side effects of a drug that will not benefit them.”
Importantly, the test uses genomic material already collected during standard diagnostic procedures and integrates with commonly used sequencing platforms. “It was important to us to create a test that could be easily adopted in the clinic,” said Piskorz.
Looking to the future, scientists hope the test will be used in diagnosis to guide treatment decisions. Tailor Bio is currently fundraising for a phase II clinical trial, scheduled to begin in 2026, which will use the test to select patients for a novel targeted therapy developed to treat tumors with specific CIN signatures.
Reference: Thompson JS, Madrid L, Hernando B, et al. Predicting resistance to chemotherapy using chromosomal instability signatures. Nat Genet. 2025:1-10. doi: 10.1038/s41588-025-02233-y
About the interviewee
Dr. Geoff Macintyre is part-time chief scientific officer at Tailor Bio and a research Group Leader at the Spanish National Cancer Research Centre. At Tailor Bio, Macintyre leads on technology and research development, where his team is building a chromosomal instability signature technology platform to generate new therapeutic and matched companion diagnostic opportunities for tumors with chromosomal instability. Macintyre’s research group develops new computational and genomics approaches to understand the earliest stages of chromosomal instability and tumor evolution with the goal of cancer prevention.
