Cause of resistance to PI3K-alpha inhibitor identified

Loss of the tumor suppressor PTEN was a frequent cause of resistance to the investigational drug BYL719, which blocks the activity of a protein called PI3K-alpha. This was found in a small sample of women with breast cancer that progressed after initially responding to BYL719 treatment. These results were presented at the American Association for Cancer Research 2014 Annual Meeting, in San Diego, California.

“Disruption of a signaling pathway called the PI3K pathway is thought to have an important role in driving a number of cancer types, including breast cancer,” said Pau Castel, a graduate student in the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center in New York, New York. “Several drugs that target PI3K proteins are currently being tested in clinical trials. One of these drugs, BYL719, which targets PI3K-alpha, has shown promising results for patients with breast cancer harboring mutations in the gene that encodes PI3K-alpha, PIK3CA. 

“Unfortunately, as for other targeted therapies, most patients treated with BYL719 eventually relapse as their breast tumors become resistant to the effects of the drug,” Castel continued. “We have found strong clinical evidence that a common way in which breast tumors become resistant to BYL719 is through loss of PTEN. We also found using a mouse model derived from these tumors that treating mice with both BYL719 and a PI3K-beta inhibitor overcame BYL719 resistance.

“These data suggest that assessment of PTEN levels could help clinicians select patients most likely to respond to BYL719 and determine which patients may benefit from the addition of a PI3K-beta inhibitor to their treatment regimen,” Castel added.

Castel and colleagues started their study by analyzing tumor samples from a patient with breast cancer who had relapsed after initially responding to treatment with BYL719 through a clinical trial. They performed sequencing of samples of the patient's tumor obtained prior to BYL719 treatment and samples of two metastatic tumors obtained after relapse. One of these metastatic tumors, obtained from the patient's lung, was resistant to BYL719 and one remained sensitive to the drug.

The researchers identified loss of the PTEN gene and mutation of the PTEN gene only in the metastatic lung tumor. Analysis of metastatic tumor samples from an additional 14 sites showed that loss of PTEN via numerous mechanisms had occurred in all samples resistant to BYL719 but that PTEN remained intact in all samples still responding to the drug.

The researchers then used cells from the metastatic lung tumor to generate a patient-derived mouse model. They found that the model recapitulated the behavior of the original metastatic lung tumor and was resistant to BYL719. Adding a PI3K-beta inhibitor to BYL719 led to tumor regression, as did monotherapy with a pan-PI3K inhibitor. 

“Our study has provided evidence that combining PI3K-alpha and -beta inhibitors or the use of a pan-PI3K inhibitor may be effective in patients who escape PI3K inhibition via loss of PTEN function,” said Castel.

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