Allosteric PI3Kα Inhibition Overcomes On-target Resistance to Orthosteric Inhibitors Mediated by Secondary PIK3CA Mutations

Abstract

PIK3CA mutations occur in ~8% of cancers, including ~40% of HR-positive breast cancers, where the PI3K-alpha (PI3Ka)-selective inhibitor alpelisib is FDA-approved in combination with fulvestrant. Although prior studies have identified resistance mechanisms, such as PTEN loss, clinical acquired resistance to PI3Ka inhibitors remains poorly understood. Through serial liquid biopsies and rapid autopsies in 39 patients with advanced breast cancer developing acquired resistance to PI3Ka-inhibitors, we observe that 50% of patients acquire genomic alterations within the PI3K-pathway, including PTEN loss and activating AKT1 mutations. Notably, while secondary PIK3CA mutations were previously reported to increase sensitivity to PI3Ka-inhibitors, we identified emergent secondary resistance mutations in PIK3CA that alter the inhibitor binding pocket. Some mutations had differential effects on PI3Ka-selective vs. pan-PI3K inhibitors, but resistance induced by all mutations could be overcome by the novel allosteric pan-mutant-selective PI3Ka-inhibitor RLY-2608. Together, these findings provide insights to guide strategies to overcome resistance in PIK3CA-mutated cancers.

Predictive, preventive, and personalized medicine in breast cancer: targeting the PI3K pathway

“…Despite these advancements, challenges persist, including the emergence of resistance to PI3K inhibitors and the intricate regulatory mechanisms within the PI3K signaling pathway [ 173 ]. Ongoing research efforts aim to unravel this complexity, refining preventive strategies and providing insights to further advance breast cancer treatments [ 6 , 174 ].…”

Molecular Targeting of the Phosphoinositide-3-Protein Kinase (PI3K) Pathway across Various Cancers

“…Liquid biopsies and autopsies were used to assess mutations and alterations, and it was found that a change in the drug-binding site caused a newly acquired PI3K-resistant pathway. However, allosteric PI3K inhibition could overcome this resistance mechanism [245].…”

“…In a recent paper by Varkartis et al, approximately 50% of acquired resistance to alpelisib was due to PTEN loss or the activation of AKT1 mutation and secondary resistant mutations that alter the PI3K binding pocket, reducing its efficacy [245].…”

Combination Therapy Approach to Overcome the Resistance to PI3K Pathway Inhibitors in Gynecological Cancers

“…However, secondary PIK3CA mutations and acquired activating AKT mutations have been suggested as mechanisms of resistance. For instance, the PIK3CA Q859 and W780 mutations, and AKT E17K/Q79K mutations, confer resistance to inavolisib and alpelisib in breast cancer patients with baseline PIK3CA mutations (H1047R, E542K/E545K) [ 35 ]. This study provides further indication that some PIK3CA mutations may actually drive resistance, rather than sensitivity, to PI3Kα inhibitors.…”