Researchers have discovered that resistance to PI3K-alpha inhibitors and reduced drug binding in patients with breast cancer may be driven by secondary PIK3CA mutations and so may be effectively treated with a novel class of PI3K-alpha inhibitors designed to bind to different parts of the target, according to a study published by Varkaris et al in Cancer Discovery.
Background
Mutations in the PIK3CA gene that lead to elevated production of the PI3K-alpha protein may be among the most frequent alterations found in tumors, including approximately 40% of hormone receptor–positive breast cancers.
Patients with these mutations are often treated with PI3K-alpha inhibitors such as alpelisib—the first drug targeting PI3K-alpha to receive approval for use in the United States in 2019. However, tumors with PIK3CA mutations may eventually develop resistance to the agents.
Study Methods and Results
In the recent study, the researchers collected the blood and/or tumor samples of 39 patients with advanced breast cancer that developed resistance to the PI3K-alpha inhibitors alpelisib or inavolisib. They then analyzed the patients’ circulating tumor DNA—which was isolated from the blood to identify newly acquired genetic mutations arising in the tumors over the course of treatment—and sequenced the DNA of 100 tissue specimens collected from the autopsies of eight patients with metastatic breast cancer who had previously given their consent.
The researchers also examined the effects of the acquired mutations that were found in tumor cell line models.
“We were able to confirm that some of these alterations are indeed responsible for limiting the effectiveness of PI3K-[alpha] inhibitors,” revealed co–lead study author Ferran Fece de la Cruz, PhD, a postdoctoral fellow at the Mass General Cancer Center. “We observed that 50% of patients acquire genomic alterations within the PI3K pathway that led to reactivation of the signaling pathway—including mutations that impact not only PI3K-[alpha] but also other pathway components such as PTEN and AKT,” he added.
Some of the acquired mutations affecting PI3K-alpha were found to alter the structure of the region where alpelisib or inavolisib bound, potentially explaining why patients with these mutations were not able to continue benefiting from the treatment. Of note, the researchers determined that a different class of PI3K-alpha inhibitors known as allosteric pan-mutant–selective inhibitors—which bind to a different region of the mutant protein—were still effective, even in the presence of these acquired mutations.
Conclusions
“These findings suggest that this new class of PI3K-[alpha] inhibitors could represent an important therapeutic option for these patients,” highlighted co–lead study author Andreas Varkaris, MD, PhD, a clinical investigator at the Termeer Center for Targeted Therapy at the Mass General Cancer Center.
“As more and more patients are treated with PI3K-[alpha] inhibitors, we are studying how frequent these acquired genomic alterations are,” emphasized co–senior study author Dejan Juric, MD, Director of the Termeer Center for Targeted Therapies & Investigational Therapeutics Program at Mass General Cancer Center. “Moreover, a significant portion of our patients do not present any of these mutations at the time of disease progression, indicating the puzzle is far from being completed,” he concluded.
Disclosure: For full disclosures of the study authors, visit aacrjournals.org.
