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TKI Cancer Treatment Resistance Linked to Common Germline Variant in East Asian Populations

By Andrea Anderson

NEW YORK (GenomeWeb News) – A Singapore-led team has identified a germline polymorphism that appears to account for reduced drug response in some East Asian cancer patients treated with tyrosine kinase inhibitors.

As they reported online yesterday in Nature Medicine, the researchers used massively parallel paired-end digital tag sequencing to look for germline variations associated with reduced response to TKI drugs, which are used to combat certain cancers marked by excess kinase activity, including some forms of chronic myelogenous leukemia and non-small cell lung cancer.

Using blood samples from five CML patients whose cancers did or did not respond to TKI treatment, the team found a resistance-related deletion polymorphism in BIM, a gene that normally helps spur on apoptosis following TKI treatment.

While this deletion appears to be a fairly common germline variant in East Asian populations — turning up in just over 12 percent of healthy individuals tested in that population — it has not been found with any regularity in populations from Europe or Africa.

The investigators have already started looking for alternative treatments for individuals with the variant, focusing on ways to restore the apoptotic activity that's lost when deletion-containing BIM isoforms are expressed. Indeed, their preliminary cell line experiments hint that it is possible to combat TKI resistance in those carrying the BIM deletion by augmenting TKI treatment with drugs known as BH3 mimetics.

"Ideally we would like to conduct clinical trials using a combination of TKIs and BH3 mimetics in patients with the polymorphism who have failed or become resistant to standard TKI therapy," co-corresponding author S. Tiong Ong, a medical oncology researcher at Duke-National University of Singapore, told GenomeWeb Daily News in an e-mail message.

TKI drugs such as imatinib (marketed as Gleevec by Novartis) or gefitinib (marketed by AstraZeneca under the brand name Iressa) have been successfully used to treat many kinase-driven cancers that did not respond to cancer drugs used in the past, study authors explained. But a subset of cases — around 20 percent — remain resistant to TKI drugs.

To look into the genetic basis of this resistance, the team did paired-end digital tag sequencing, or DNA-PET, with Life Technologies' SOLiD platform to look for germline structural variants that might help explain treatment response heterogeneity, using blood samples from two imatinib-sensitive and three imatinib-resistant CML patients.

"We correlated the structural variations detected by DNA-PET with clinical resistance to Gleevec, and picked out SVs which were found only in samples from resistant patients," Ong said in his e-mail.

A 2,903 base pair deletion polymorphism in an intron of the BIM gene coincided with TKI treatment resistance, they found.

The germline polymorphism appears to be fairly common in East Asian populations, turning up with around 12 percent carrier frequency in their screening experiments on thousands of healthy individuals. But the BIM deletion was not found in any individuals from African or European populations.

In addition, retrospective analysis of more than 200 CML patients enrolled in two cohorts from Singapore and Malaysia or Japan indicated that individuals with the BIM deletion were almost three times as likely to show imatinib resistance than those without the polymorphism.

Similarly, in East Asian non-small-cell lung cancer patients with EGFR mutations, the researchers found evidence for shorter progression-free survival in individuals with the BIM polymorphism who received TKI treatment compared to those without the deletion.

The team's cell line and other experiments indicated that BIM deletion affects treatment outcome by influencing BIM splicing patterns in a way that alters the apoptosis-related interactions of the resulting protein.

Whereas cells without the deletion typically expressed exon 4 in the presence of TKI compounds, cells with the polymorphism predominantly expressed exon 3 of the gene, which does not code for a domain necessary for apoptosis.

"The BIM deletion polymorphism results in the splicing (and expression) of BIM isoforms lacking a critical BH3 domain that is required for BIM apoptotic function," Ong said.

"Without this domain, the BIM protein isoforms which are produced in response to the TKI are no longer capable of killing the cancer cells," he added.

Moreover, the researchers found that even a single copy of the polymorphism was enough to prompt TKI resistance in CML and EGFR-mutation containing NSCLC cell lines.

Given their mechanistic findings, the team speculated that it might be possible to curb this intrinsic TKI treatment resistance by combining TKI treatment and therapy with so-called BH3 mimetics, compounds that restore the apoptosis promoting activity missing from cells expressing exon 3 rather than exon 4 of the BIM gene.

Preliminary experiments in CML cell lines supported that prediction, since treatment with both imatinib and the BH3 mimetic ABT-737 seemed to spur apoptosis even in the presence of the BIM deletion.

The team has not yet looked at how the TKI treatment resistance differences associated with the BIM polymorphism relate to overall survival patterns in patients, if at all. Ong noted that such studies are complicated by the fact that individuals who initially show TKI resistance often receive other treatments later on, making direct comparisons difficult.

Still, he and his colleagues hope to do prospective controlled clinical trials to look more closely at such questions.

They are also interested in doing clinical trials to explore the effectiveness of combined BH3 mimetic and TKI therapy for individuals with inherent resistance related to the BIM polymorphism or for patients who have become resistant to the inhibitors through another mechanism.

BH3 mimetics have not yet secured approval from the US Food and Drug Administration, Ong said, but are being tested in clinical trials for other cancer types.

In addition, working with collaborators from the Genome Institute of Singapore and A*STAR's commercialization arm, Exploit Technologies Private Limited, Ong and his colleagues are developing a kit that would make it feasible to routinely test East Asian patients for germline mutations in BIM.

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