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PGx Highlights from the American Association for Cancer Research Meeting


The annual meeting of the American Association for Cancer Research, held last week in Chicago, featured a number of studies related to genomically guided cancer treatments.

The following is a roundup of some of the meeting's pharmacogenomics highlights.

Glioblastomas Harbor Different EGFR Mutations than Lung Cancers; May Respond to Lapatinib

Researchers led by Ingo Mellinghoff at Memorial Sloan-Kettering Cancer Center presented data from a study indicating that EGFR mutations that occur in
glioblastoma differ from those that occur in lung cancers, which may explain why glioblastoma patients do not respond to EGFR inhibitors such as Genentech's Tarceva (erlotinib).

The results indicate, however, that these tumors might respond to GlaxoSmithKline's Tykerb (lapatinib), an EGFR inhibitor with a different binding conformation than erlotinib.

The study, which was also published in Cancer Discovery last week, found that EGFR mutations in glioblastoma were almost exclusively found in the extracellular part of the receptor, while EGFR mutations in lung cancer are typically located in the intracellular part of the receptor, the kinase domain.

While lung cancers with EGFR mutations respond to erlotinib, the drug has only shown limited effectiveness for the treatment of glioblastoma. However, the study showed that glioblastoma cell lines that harbor EGFR EC mutations are more sensitive to so-called type 2 EGFR kinase inhibitors, like lapatinib, whereas lung cancer cell lines with EGFR KD mutations respond better to erlotinib, a type 1 EGFR kinase inhibitor.

The paper notes that previous studies have identified different receptor conformations between the two types of inhibitors, which may explain the difference in response. Specifically, in complex with lapatinib, the EGFR KD is in an inactive, or type 2, conformation, but when in complex with erlotinib, the EGFR KD adopts an active, or type 1, conformation.

Based on this information, "we hypothesized that conformation-specific binding to EGFR might explain the differential response of GBM cell lines with EGFR EC mutants to these two compounds," the authors wrote. "If correct, lapatinib … should also show superior activity against EGFR EC mutants than erlotinib."

The researchers conducted a multicenter clinical trial in which 44 patients with recurrent GBM received 750 mg of lapatinib orally for seven days prior to surgery, but the study failed to prolong progression-free survival in these patients.

However, Mellinghoff said in a press conference at AACR discussing the results that his team has received the "green light" from GSK to conduct another clinical trial with a higher lapatinib dose in GBM patients with EGFR-mutant tumors.

KRAS Mutation, Amplification Status Predicts Response to Antifolate Therapies in NSCLC

Researchers from Quintiles and the University of Western Ontario presented data in a late-breaking poster session on a study that investigated the relationship between antifolate sensitivity and KRAS mutation/amplification status in non-small cell lung cancer.

While lung cancer with KRAS mutations do not respond well to targeted therapies, the researchers found that these mutations may predict response to treatment with antifolates, as long as the number of mutant genes is not amplified.

In the study, the researchers treated human NSCLC cell lines — KRAS wild type, KRAS-mutant nonamplified, and KRAS-mutant amplified — with the antifolates methotrexate or pemetrexed.

They found that the KRAS-mutated cell lines responded well to both drugs, but this response was not seen if the number of copies of the KRAS-mutant gene was amplified or if the KRAS was wild type.

"Overall, antifolates represent a novel method to target KRAS and as such should be investigated further for use in this subtype of NSCLC," the researchers note in their poster abstract. "As clinical evidence emerges, both KRAS mutation and amplification status should be incorporated for patient stratification prior to antifolate treatment."

MEK1 Not Linked to Resistance to BRAF Inhibitors in Melanoma

Researchers from the Jonsson Cancer Center at the University of California, Los Angeles, found that MEK1 mutations are not associated with resistance to BRAF inhibitors in melanoma — a finding counter to what they expected.

The researchers, led by UCLA's Roger Lo, hypothesized that because MEK1 mutations are frequently associated with BRAF mutations — around 15 percent of the time — this might explain the fact that melanoma patients who initially respond to BRAF inhibitors eventually acquire resistance. Their results proved that this is not the case, however.

Lo and his team analyzed tumor samples from 31 melanoma patients treated with a BRAF inhibitor. Of these patients five carried mutations in both MEK1 and BRAF before the cancer was treated. Three of these five patients showed objective tumor responses, consistent with the overall 60 percent response frequency seen in BRAF-mutation positive patients. Furthermore, no MEK1 mutations were found in melanomas that progressed, except when it was already identified at baseline.

The researchers further verified these conclusions using melanoma cell lines grown in the laboratory.

Lo said in a statement that he and his colleagues were “surprised" to find that patients with double BRAF/MEK1-mutated melanomas can respond to BRAF inhibitors as well as patients with single BRAF-mutated melanomas.

“These findings tell oncologists that these two groups of patients — those patients with BRAF-mutated melanomas and those with BRAF and MEK1-mutated melanomas — can be expected to respond similarly well to BRAF inhibitors or the combination of BRAF inhibitors plus MEK inhibitors,” Lo said.

He added that he and his colleagues are "pushing forward to uncover biomarkers of BRAF inhibitor sensitivity or resistance and hope to use them as a guide to formulate therapeutic strategies.”

The results of the study were also published in Cancer Discovery.

Foundation Medicine Uses Sequencing Platform to ID Potential Therapies for NSCLC, Prostate Cancer

In two posters presented at AACR, Foundation Medicine demonstrated how its sequencing-based platform can identify mutations in tumors that could help guide treatment with targeted therapies.

In one poster, researchers from Foundation, the Dana-Farber Cancer Institute, and elsewhere used sequencing to identify a novel oncogenic KIF5B-RET fusion gene in a subset of non-small cell lung cancer patients lacking other known driver mutations. According to the researchers, the findings "suggest that RET kinase inhibitors should be tested in prospective clinical trials for therapeutic benefit in NSCLC patients bearing KIF5B-RET rearrangements."

The researchers noted in the poster abstract that they were seeking to find treatment options for NSCLC patients who do not have alterations in known driver genes, such as EGFR, KRAS, ERBB2, BRAF, ALK and ROS1.

They first sequenced a NSCLC specimen from a 44 year old Caucasian never-smoker using Foundation's targeted sequencing panel, which included 145 cancer-relevant genes plus 37 introns from 14 genes frequently rearranged in cancer.

They identified an 11-Mbp inversion on chromosome 10 that generated "a novel gene fusion joining exons 1-15 of KIF5B to exons 12-20 of RET." After screening an additional 117 NSCLC patients, one patient was found to have the KIF5B-RET fusion via sequencing. The researchers also evaluated 526 tumors from never/former limited smokers and identified 10 additional positive patients.

In cell line studies, the researchers found that KIF5B-RET Ba/F3 cells were "sensitive to sunitinib, sorafenib and vandetinib, multi-targeted kinase inhibitors that inhibit RET, but not gefitinib, an EGFR kinase inhibitor."

In the second poster, researchers from the company and Weill Cornell Medical College of Cornell University used Foundation's sequencing approach to identify targetable molecular alterations in highly aggressive prostate cancer, using formalin-fixed paraffin embedded samples.

The researchers looked at 21 prostate cancer samples, 18 neuroendocrine prostate cancer samples, and 18 benign prostate samples. They identified 133 mutations in 30 genes, with 87 percent of cancer samples containing at least one mutation.

A TMPRSS2-ERG fusion was present in 31 percent of cases. Other recurrent high-confidence alterations included: gain of MYC (9 percent of cases); gain or substitution/indel of AR (43 percent); deletion or substitution/indel of PTEN (23 percent), RB1 (20 percent), or BRCA2 (11 percent); and substitution/indel of TP53 (40 percent), CTNNB1 (11 percent), PIK3CA (6 percent), or ATM (6 percent).

"The spectrum of driver mutations observed highlights potential value of comprehensive genomic profiling for targeted therapy selection in clinical care," the researchers stated in the poster abstract. "These analyses have laid the foundation for ongoing comparison with indolent [prostate cancer], and have identified potential new drug targets (e.g., PARP inhibitors for ATM and BRCA2 mutations)."

The Scan

Genome Sequences Reveal Range Mutations in Induced Pluripotent Stem Cells

Researchers in Nature Genetics detect somatic mutation variation across iPSCs generated from blood or skin fibroblast cell sources, along with selection for BCOR gene mutations.

Researchers Reprogram Plant Roots With Synthetic Genetic Circuit Strategy

Root gene expression was altered with the help of genetic circuits built around a series of synthetic transcriptional regulators in the Nicotiana benthamiana plant in a Science paper.

Infectious Disease Tracking Study Compares Genome Sequencing Approaches

Researchers in BMC Genomics see advantages for capture-based Illumina sequencing and amplicon-based sequencing on the Nanopore instrument, depending on the situation or samples available.

LINE-1 Linked to Premature Aging Conditions

Researchers report in Science Translational Medicine that the accumulation of LINE-1 RNA contributes to premature aging conditions and that symptoms can be improved by targeting them.