Sensitizing Colorectal Tumors to Chemotherapy

Although colorectal tumors with microsatellite instability (MSI) are usually considered to have a poor response to 5-fluorouracil–based chemotherapy, researchers have identified a subset that actually respond well to chemotherapy. These tumors express a dominant-negative form of the chaperone HSP110, according to the February issue of Gastroenterology.

Colorectal cancer (CRC) is a heterogeneous disease; cells of most tumors (80%–85%) have chromosome instability, and significant fraction (15%–20%) have widespread instability at DNA repeats, or MSI. Patients with MSI tumors have better prognoses than those without, but these tumors do not usually respond to 5-fluorouracil–based chemotherapy.

Chaperone proteins such as HSP110 promote the survival of CRC cells. An HSP110 truncation mutant (HSP110DE9) is expressed by some CRC cells with MSI; it is generated from an aberrantly spliced mRNA that results from large deletions of the T17 repeat with intron 8 of the gene that encodes HSP110 (HSPH1). HSP110DE9 interferes with the chaperone activity of HSP110 in a dominant-negative manner to sensitize CRC cells to 5-fluorouracil and oxaliplatin.

Ada Collura et al. investigated whether patients with colorectal tumors that have MSI and also large deletions of the T17 repeat, which cause them to express HSP110DE9, have better responses to chemotherapy than patients without the T17 deletions.

Collura et al. searched for T17 deletions in tumor samples from 329 patients with stage II or III colorectal tumors with MSI, and compared them with patient outcomes. The authors found that most deletions in T17 were biallelic, and resulted in increased ratios of HSP110DE9:HSP110 in tumor samples.

A high percentage of patients (94%) with stage II–III tumors with large HSP110 T17 deletions (≥5 bp) survived for 5 years, relapse-free, after chemotherapy. Among patients with small or no deletions (≤4 bp), only 64% survived for this time period.

Survival analysis of patients with stage II or III colorectal tumors with MSI CRC patients treated with chemotherapy. Patients were classified based on the size of deletion in the T17 intronic repeat.

Survival analysis of patients with stage II or III colorectal tumors with MSI CRC patients treated with chemotherapy. Patients were classified based on the size of deletion (L, long [blue] or S, short [green]) in the T17 intronic repeat.

As expected, because of the chemosensitizing effect of HSP110DE9, deletions in T17 did not affect survival of patients with stage II–III tumors who did not receive chemotherapy.

Collura et al. conclude that patients with large T17 deletions are a minority but nevertheless an important fraction (about 25%) of patients with colorectal tumors with MSI who appear to benefit from 5-FU–based adjuvant chemotherapy. The authors found it particularly interesting that the association between survival and T17 deletion was also significant in a subgroup of patients treated with only 5-fluorouracil.

Collura et al. also showed that tumor mutations in 15 other genes, including some that might play a role in drug response (such as ATR, ATM), had no prognostic significance, indicating the unique role of HSP110 in response to chemotherapy. However, Collura et al. did not assess whether the association between HSP110 T17 deletion and patient survival was independent of other molecular features, such as BRAF mutations or the CpG island methylator phenotype. These genetic features have also been associated patient outcome and colorectal tumor MSI.

The findings of Collura et al. could lead oncologists to reconsider the concept that CRCs with MSI do not respond to 5-fluorouracil–based adjuvant chemotherapy, and increase individualization of treatment of patients with CRC.

About Kristine Novak, PhD, Science Editor

Dr. Kristine Novak is the science editor for Gastroenterology and Clinical Gastroenterology and Hepatology, both published by the American Gastroenterological Association. She has worked as an editor at biomedical research journals and as a science writer for more than 12 years, covering advances in gastroenterology, hepatology, cancer, immunology, biotechnology, molecular genetics, and clinical trials. She has a PhD in cell biology and an interest in all areas of medical research.
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