Loss of PTEN in Breast Cancer Led to PI3K Inhibitor Resistance

Loss of the tumor suppressor PTEN was found to be a frequent mechanism of resistance to treatment with the PI3K-alpha inhibitor, BYL719, in women with breast cancer.

Researchers tested the safety and efficacy of BYL719 in a phase I clinical trial that enrolled metastatic breast cancer patients whose primary tumors harbored a mutation in the alpha isoform of the catalytic subunit of the PI3K complex.

Pau Castel, graduate student in the Human Oncology and Pathogenesis Program at Memorial Sloan-Kettering Cancer Center in New York, and colleagues analyzed tumor samples from patients on the trial. Castel presented the data at a press conference at the annual meeting of the American Association of Cancer Research, held April 5-9, 2014.

PI3K inhibitors are currently being tested in clinical trials to treat women with advanced breast cancer, as activating mutations in the PIK3CA gene (which encodes the catalytic subunit of the PI3K complex), have been frequently found in breast cancer.

The loss of the PTEN gene was identified using exome and whole-genome sequencing from the tumor of a patient with PI3KCA-mutated metastatic breast cancer who initially had a 7 month response to BYL719, followed by rapid disease progression and death. The authors compared two metastatic disease tumor samples from the patient-a lung metastasis that had progressed following BYL719 treatment and a periaortic lesion that was still responding to BYL719 at time of death-to the patients’ primary tumor sample not exposed to BYL719. PTEN loss was observed in the drug-resistant lung lesion, but not in the responding metastatic lesion or the primary tumor lesion.

Preliminary analyses of nine other patient tumor samples from this first-in-human clinical trial of BYL719 in breast cancer showed that two of these patients had PTEN loss when their tumor stopped responding to the therapy.

With other metastatic tumor samples available, Castel and colleagues performed targeted exome sequencing on these, and found a consistent loss of PTEN only in the tissues that had become resistant to the PI3K-alpha inhibitor, but not in the tumor samples that showed continued evidence of response to BYL719. PTEN mutations varied in the tumor samples from frameshift mutations to deletion and splice site mutations. Loss of PTEN was also confirmed by testing for protein expression in the tissue with immunohistochemistry (IHC).

Using an in vitro model, the researchers showed that cell lines sensitive to BYL719 in which PTEN was subsequently inhibited, became resistant to the drug.

Then, making a xenograft mouse model from the initial patient’s PTEN-null lung lesion, the researchers demonstrated that inhibiting both PI3K-alpha and PI3K-beta, both components of the PI3K holoenzyme, could overcome the resistance to BYL719 alone.

Aberrant PI3K signaling has been documented in a variety of tumor types and a driver of cancer. PTEN loss may be a relatively common resistance mechanism in tumors exposed to a PI3K-alpha inhibitor.

“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,” said Castel in a statement.

Tumors are heterogenic and dynamic, evolving throughout the course of therapy, said Pau during the press briefing. “So our therapies need to evolve as well.”

The current study suggests that combination therapy is necessary to overcome this resistance. Particularly, the combination of PI3K-alpha and PI3K-beta inhibitors, or a pan-PI3K inhibitor that targets the different PI3K subunits, may be a way to at least partially overcome the PTEN loss resistance mechanism. Still, it is not clear whether upfront combination therapy to preempt potential future resistance or whether changing or adding therapy as the tumor response to therapy evolves is the best approach.

This is the type of study that teaches us where the cancer field needs to go in designing therapy strategies, said Louis M. Weiner, MD, director of the Lombardi Comprehensive Cancer Center at Georgetown University, who moderated the press briefing.

“[This study] exemplifies an emerging field that is the understanding of the heterogeneity and landscape of mutations within tumors and their evolution,” said Weiner.

Reference

Castel P, Juric D, Won H, et al. Loss of PTEN leads to clinical resistance to the PI3Kα inhibitor BYL719 and provides evidence of convergent evolution under selective therapeutic pressure. American Association for Cancer Research Annual Meeting 2014; April 5–9, 2014; San Diego. Abstr LB-327.