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Pharma-led Group IDs Recurrent, Druggable Mutations in Liver Cancer

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The Asian Cancer Research Group, led by Pfizer, Eli Lilly, and Merck, has used whole-genome sequencing to identify recurrent, druggable mutations in hepatocellular carcinoma.

The team sequenced the whole genomes of 88 matched tumor/normal samples of HCC and found that around 9 percent of patients had a mutation in JAK1, a gene for which there are drugs approved to treat myeloproliferative diseases. Additionally, they identified other potentially actionable mutations, including amplifications of FAK, CCND1, FGF19, and PARP, and inactivating mutations in BRCA1 and 2.

The results, published last month in Genome Research, demonstrate that next-gen sequencing is "not only a powerful tool to study disease biology and identify new drug targets, but also provides opportunities for promptly translating scientific discoveries into improvements in patient care," the authors wrote.

Mao Mao, president of the Asian Cancer Research Group and research fellow at Pfizer Oncology, told Clinical Sequencing News that the JAK1 mutation was "a somewhat surprising result because it was [previously] unknown" in HCC.

Additionally, the two major oncogenic pathways the team identified—the JAK pathway and the beta catenin pathway — are not typically seen in solid tumors, Mao said.

Other solid tumors often have mutations in the BRAF, EGFR, MAPK pathways, said Mao. "HCC is unique," he said. "It's a very unique cell type and a very unique carcinogen."

He said the group is also working on transcriptome sequencing studies of the samples and larger sequencing studies of HCC as well as sequencing studies of gastric and lung cancers.

Of the 88 patients, 81 were carriers of the hepatitis B virus, with chronic HBV or cirrhosis. For each of them, the team created two libraries with different insert sizes — a 170-base pair insert library and an 800-base pair insert library — to ensure enough coverage to capture structural variants.

In total, the team found 823,835 somatic SNV mutations, of which 5,015 are predicted to affect protein-coding regions. A total of 3,739 genes were mutated, including 809 genes with multiple protein-altering mutations. The researchers identified over 35,000 small deletions and 22,000 small insertions, 302 of which affect protein-coding regions in 285 genes.

Deletions were found in known oncogenes such as CTNNB1, MDM2, IL6ST, as well as in known tumor suppressors including ARID1A, AXIN1, PTEN, RB1, and TP53.

Additionally, the researchers identified 399 genomic HBV integration events affecting 115 coding genes and 4,314 somatic structural variants, including 260 gene fusions.

The most significantly mutated genes included three genes previously known to be mutated in HCC: TP53, CTNNB1, and AXIN1; two genes frequently mutated in other cancer types: JAK1 and LRP1B; and six genes not previously reported to be mutated in HCC: EPS15, SLC10A1, CACNA2D4, ADCY2, FAM5C, and COL11A1.

Doing a pathway analysis implicated two major pathways: the Wnt/beta catenin pathway and the STAT/JAK pathway, which were mutated in 62.5 percent and 45.5 percent of tumors, respectively.

Mutated genes in the Wnt/beta-catenin pathway included CTNNB1. Over 15 percent of tumors harbored protein-altering mutations in this gene. Additionally, around 9 percent of tumors had protein-altering mutations to one of three negative regulators of CTTNB1.

The second major pathway, and the one with the most immediate treatment implications, was the JAK/STAT pathway. Around 45.5 percent of tumors had mutations in this pathway, including 9 percent of tumors that had activating mutations of the JAK1 oncogene.

The researchers studied the consequences of the JAK1 activating mutations in cell lines. They found that not only did those mutations induce cell growth, but the mutated cells were sensitive to ruxolitinib, a JAK1/2 inhibitor marketed by Incyte Pharmaceuticals and Novartis as Jakafi and Jakavi, respectively, for the treatment of intermediate or high-risk myelofibrosis.

The JAK1 mutant cells showed "potent growth inhibition" in response to the drug, while the wild-type cells were only partially affected, the authors wrote.

Aside from the JAK1 mutations, the group identified other actionable mutations, including CCND1 amplifications in 4.5 percent of tumors and CDKN2A deletions in 10.2 percent of tumors. Currently, Pfizer's investigational drug palbociclib is being tested in advanced breast cancers for patients with CCND1 amplifications and/or the loss of p16, suggesting these HCC tumors could be candidates for trials of the drug as well, the authors wrote.

Around 26.1 percent of the HCC tumors had FAK amplifications, for which there are currently two inhibitors in phase 1 trials. The PARP1 gene is amplified in 18.2 percent of cases and there are mutations in BRCA1 and BRCA2 in 1.1 percent and 5.7 percent of cases, respectively, suggesting that these tumors may be sensitive to PARP inhibitors.

Finally, the team found FGF19 amplifications in 4.5 percent of tumors and tested in cell lines an FGFR small molecule inhibitor known as PD173074 that is being developed by Pfizer. They found that the cells with the FGF19 amplifications or with over-expression of either the FGF19 or FGF4 genes showed increased sensitivity to the drug.

Another drug, brivanib alaninate, is already being developed for HCC by Bristol-Myers Squibb, and is a dual inhibitor of VEGFR and FGFR. Currently, it is being evaluated in phase 3 HCC trials, and the authors suggested this compound as well as other FGFR inhibitors could be effective in HCC patients with these amplifications and over-expressions.

Mao said that the Asian Cancer Research Group's goal is not to pursue functional studies and clinical trials of these compounds, but rather to generate data on the genomes of these cancers and make it available to the broader scientific community. However, he noted that Pfizer and other drug companies could pursue further development of these drugs.

Additionally, the results could help shorten the timeline of drug development for HCC, the authors said, since the sequencing indicated a number of potentially effective compounds that are already in late-stage preclinical or clinical development.

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