Drugs Targeting Kinase Fusions May Boost Outcomes in Some Microsatellite-Instable Colorectal Cancers

By Marilynn Larkin

May 31, 2022

NEW YORK (Reuters Health) - In patients with microsatellite instable colorectal cancer (MSI CRC) harboring druggable kinase fusions (KFs), combination therapy targeting specific fusions along with immune checkpoint blockade may improve long-term outcomes, a genomic analysis suggests.

"A subset of CRC occurs in the setting of an underlying defect in mismatch repair, leading to MSI, which is characterized by variation in the length of microsatellite repeats," Dr. Shridar Ganesan and Dr. Subhajyoti De, both of Rutgers Cancer Institute of New Jersey, told Reuters Health by email.

Currently, only about half of MSI CRC patients respond to immune checkpoint blockade, which is used routinely among patients with advanced disease, they note in JCO Precision Oncology, of which Dr. Ganeson is associate editor. This creates an unmet need for other treatment approaches, which is what prompted the study.

"We thought initially that the increased incidence of kinase fusions in mismatch repair-deficient colon cancers may have something to do with the role of mismatch repair in enforcing the accuracy of homology-mediated DNA repair," said Drs. Ganesan and De. "But the data clearly showed this was not the case."

"Only mismatch repair(-deficient) colon cancers, but not mismatch repair-deficient uterine cancers, had an elevated incidence of oncogenic fusions, suggesting there was something special about the colon environment," they explained. "This led us to find that the microbiome of the colon may lead to the production of metabolites that can induce oxidative damage in the colon cells; the loss of mismatch repair function then did not allow efficient repair of these lesions, and this sets the stage for the generation of fusion genes."

"We need to do more work to determine if specific elements of the microbiome in the colon do in fact lead to generation of DNA damage in normal colon and if this can be prevented," they said. "Although our data are quite suggestive of the mechanism we propose, we have to do further work to see if this hypothesis is correct."

Drs. Ganesan, De and colleagues examined the genomic profiles of 32,218 advanced CRC tumor specimens to assess the fusion breakpoints of oncogenic alterations, including KFs (e.g., NTRK1, RET and BRAF), in microsatellite-stable and MSI CRC.

From a mechanistic standpoint, their genomic analysis revealed characteristics of the oncogenic fusion breakpoints in MSI tumors and showed that a higher mutation frequency at guanine:cytosine bases in certain introns predicted the prevalence of associated oncogenic fusions in MSI CRCs.

Further, CRCs harboring mismatch repair signatures were enriched with butyrate-producing microbial species, reported to be associated with the induction of 8-oxoguanine lesions in the intestine.

"Detailed analysis of breakpoints in MSI-associated KFs support a model in which inefficient repair and/or processing of microbiome-induced clustered 8-oxoguanine damage in MSI CRC contributes to the increased incidence of specific oncogenic fusions," the authors write.

From a potential clinical standpoint, Drs. Ganesan and De explained in their email, "In certain settings, it may be appropriate to perform assays looking for kinase fusions in colon cancers having microsatellite instability. Although immunotherapy can work well in these cancers, a good subset is initially resistant or becomes resistant, and in these cancers kinase fusions, although relatively rare, may represent an actionable target for cancer therapy that should be considered."

The study was funded by M2Gen. Dr. Ganesan is a Merck employee and, except for Dr. De, the coauthors are employed by Foundation Medicine and/or Roche or EQRX.

SOURCE: https://bit.ly/38VdzhC JCO Precision Oncology, online May 18, 2022.