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Genomic Study Presented at ASCO Explores Acquired Resistance to EGFR-targeted Lung Cancer Treatment

CHICAGO (GenomeWeb News) – An international team led by investigators from a company called the Cancer Therapeutic Innovation Group is using integrated genomics approaches to assess acquired resistance mechanisms in lung tumors treated with targeted therapy, attendees at the annual American Society of Clinical Oncology meeting heard here yesterday.

At a clinical science symposium on genetic resistance to targeted therapies, Trever Bivona, a researcher based at the University of California at San Francisco, reported on ongoing efforts to combine whole-exome and whole-transcriptome sequencing to look at samples from lung cancer patients who had become resistant to targeted treatment.

For the study so far, he and his colleagues have focused on more than a dozen non-small cell lung cancer patients whose EGFR-mutation containing tumors had become resistant to the tyrosine kinase inhibiting drug erlotinib (marketed as Tarceva by Genentech in the US).

In addition to revealing mechanisms by which tumors take on resistance to targeted treatment over time, such studies are expected to reveal telltale markers of those events, making it possible take action prior to the development of more advanced, heterogeneous, and highly mutated tumors.

Moreover, Bivona said, the sorts of mutations found might also offer hints about the biological processes askance in earlier-stage lung cancers that don't harbor currently actionable mutations.

Roughly 15 percent of non-small cell lung cancers contain EGFR mutations expected to be susceptible to targeted treatments such as erlotinib or gefitinib (also known as Iressa, from AstraZeneca), Bivona noted.

While such targeted therapies may prompt an initial tumor response, though, resistance remains a problem, he explained, leading to recurrence and lung cancer progression.

Prior research has revealed some of the genes prone to mutation during this process. For instance, a recurrent second site mutation in EGFR has been found in some tyrosine kinase inhibitor-resistant tumors. Others contain alterations associated with an uptick in activity by downstream signaling pathways or amplification of alternative receptor kinase genes, such as MET, HER2, or AXL.

Even so, Bivona noted that most studies of EGFR-targeting drug resistance in lung cancer so far have not been comprehensive. Conversely, genomic studies of tumor progression have tended to focus on certain cancer types or individual cases, rather than looking at the spectrum of mutations that appear following a specific targeted treatment scheme.

In their effort to understand the genetic adaptations that help EGFR-mutated, non-small cell lung cancers dodge tyrosine kinase inhibitors specifically, Bivona and his colleagues used a combination of whole-exome sequencing and whole-transcriptome sequencing with Illumina's HiSeq 2500 to profile pre- and post-resistance tumor biopsy samples from 13 individuals with non-small cell lung cancer.

All of the patients had been treated with the EGFR inhibitor erlotinib but had acquired resistance at a certain point after therapy.

The team's analysis of their protein-coding gene and RNA sequence data revealed known resistance-related changes such as the characteristic T790M mutation in EGFR, amplification of HER2 or MET, and up-regulation of the AXL gene or members of the PI3K-AKT signaling pathway.

But the researchers also detected previously unappreciated differences between the pre- and post-resistance tumors, both in the exome and gene expression data.

For instance, their data hinted that non-small cell lung cancer tumors still sensitive to erlotinib tend to have higher expression of genes from specific immune pathways — immune genes whose expression waned in the resistant tumors. Also down regulated during acquired resistance were apoptosis-promoting genes and genes coding for enzymes that participate in survival signaling.

The group saw copy number changes that coincided with resistance, too, Bivona said, particularly in some of the patients. In a few instances, those copy number shifts provided a peek at the number of sub-clones present within a tumor that were impervious to erlotinib.

Bivona also presented data from an index case representing a non-small cell lung cancer patient followed over time from the start of her treatment until a couple months afterward — work done to look at genomic profiles associated with treatment success profiles and with early drug resistance.

The woman's EGFR-mutated tumor was tested at the time that her targeted treatment began. Researchers also did exome sequencing and RNA sequencing on tumor samples taken about a week later and again 60 days post-treatment.

Over those two months, the team picked up on widespread gene expression changes in the woman's tumor, along with copy number changes and point mutations. While responding to erlotinib not long after treatment started, for example, the tumor tended to express genes from apoptosis promoting pathways. That expression dipped during her subsequent resistance to the therapy.

"We documented the feasibility, safety, and utility of this strategy to establish initial drug efficacy at the molecular level prior to any radiographic evidence of response," Bivona and several of the same co-authors noted in a related poster, also presented at this week's meeting.

"Additional, serial integrated genomic analysis is ongoing in the index patient and others on therapy to enhance the management of NSCLC patients on targeted therapy."

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