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Cervical Cancer Exomes Point to Potentially Targetable HER, PIK3CA Pathway Changes

NEW YORK – A team from the US and Italy tracked down potential treatment targets in a subset of cervical carcinoma cases using exome sequencing.

For a paper published online yesterday in the Proceedings of the National Academy of Sciences, researchers at the Yale University School of Medicine, Magna Graecia University in Italy, and elsewhere did exome sequencing on dozens of cervical cancer tumor, patient-derived cervical cancer cell line, and matched normal samples from 69 women with advanced or recurrent forms of the disease.

Along with recurrent alterations affecting cell cycle, chromatin, and apoptosis-related pathways — and somatic changes consistent with APOBEC cytidine deaminase enzyme mutagenesis — the exome sequences revealed frequent activating mutations in the ERBB2 and PIK3CA signaling pathways, prompting the team to speculate that up to 70 percent of cervical carcinomas may contain targetable alterations in the ERBB2/PIK3CA/AKT/mTOR pathways.

"These data help define the genetic landscape of cervical cancer and provide a strong preclinical rationale for clinical trials targeting HER2/PIK3CA/AKT-activating mutations with drug combinations in a large subset of metastatic or recurrent cervical cancer patients," Yale University researchers Alessandro Santin and Joseph Schlessinger, the study's co-senior authors, and their colleagues wrote.

In their initial experiments with cervical cancer cell line and xenograft models, for example, the investigators tracked the activity of afatinib or neratinib (Boehringer Ingelheim's Gilotrif and Puma Biotechnology's Nerlynx, respectively), known as "pan-HER" tyrosine kinase inhibitors, as well as the PIK3CA inhibitor copanlisib (Aliqopa from Bayer).

In both the in vitro cell line experiments and in vivo mouse models, for example, they found that afatinib/neratinib given individually did show activity against the almost 6 percent of tumors with ERBB2 domain mutations.

The compounds targeting the PIK3CA pathway appeared to have transient activity in the mouse xenograft models when used individually, the team reported, but appeared to prompt more sustained responses when used together in mice carrying tumors with ERBB2/PI3K/AKT/mTOR alterations.

"Overall," the authors wrote, "these data suggest that afatinib and neratinib, [two US Food and Drug Administration]-approved drugs in lung and breast cancer patients, may represent a potentially valid therapeutic options for patients harboring ERBB2-mutated advanced/recurrent cervical cancers."

For their analyses, the researchers focused on 69 women with advanced cervical cancer, using Illumina HiSeq instruments to sequence protein-coding portions of the genome captured with a NimbleGen/Roche exome capture reagent in 54 fresh frozen cervical carcinoma tumors, 15 primary cell lines developed from tumors, and 56 matched normal samples.

Many of the cervical cancer cases were positive for type 16 or 18 human papillomaviruses, the team noted, and included both adenocarcinomas and squamous cell carcinomas.

The researchers uncovered recurrent missense mutations in almost two dozen genes in the cervical cancers, along with a dozen common copy number gains and some 40 recurrent copy number losses.

Both the single variant and copy number changes tended to fall in specific pathways, they noted, including pathways involved in chromatin remodeling, cell cycle regulation, apoptosis, tumor-immune system interactions, and signaling by ERBB2, PIK3CA, and related genes.

When the team took a closer look, it found that around 71 percent of the tumors profiled for the study contained activating ERBB2, PIK3CA, AKT, mTOR alterations, hinting that it might be possible to thwart tumor growth by targeting the HER or PIK3CA pathways alone or in parallel. 

"While cervical cancer patients with early versus advanced stage disease have different treatment options and survival outcomes," the authors reported, "preclinical in vitro and in vivo data suggest that ERBB2/PI3K/AKT/mTOR pathway-deranged tumors may be 'targetable' in a large subset of cervical cancer patients by using pan-HER and PIK3CA inhibitors."