RTK-Dependent Inducible Degradation of Mutant PI3Kα Drives GDC-0077 (Inavolisib) Efficacy

Abstract

PIK3CA is one of the most frequently mutated oncogenes; the p110α protein it encodes plays a central role in tumor cell proliferation. Small molecule inhibitors targeting the PI3K p110α catalytic subunit have entered clinical trials, with early-phase GDC-0077 studies showing antitumor activity and a manageable safety profile in patients with PIK3CA-mutant breast cancer.However, preclinical studies have shown that PI3K pathway inhibition releases negative feedback and activates receptor tyrosine kinase signaling, reengaging the pathway and attenuating drug activity. Here we discover that GDC-0077 and taselisib more potently inhibit mutant PI3K pathway signaling and cell viability through unique HER2-dependent mutant p110a degradation. Both are more effective than other PI3K inhibitors at maintaining prolonged pathway suppression. This study establishes a new strategy for identifying inhibitors that specifically target mutant tumors by selective degradation of the mutant oncoprotein and provide a strong rationale for pursuing PI3Kα degraders in patients with HER2-positive breast cancer. SignificancePI3K inhibitors, GDC-0077 and taselisib, have unique mechanism of action; both inhibitors lead to degradation of mutant p110a protein. The inhibitors that have the ability to trigger specific degradation of mutant p110a without significant change in wildtype p110a protein may result in improved therapeutic index in PIK3CA mutant tumors.

Oncogenic mutations ofPIK3CAlead to increased membrane recruitment driven by reorientation of the ABD, p85 and C-terminus

“…PIK3CA mutant selective inhibitors would likely have major advantages in cancer treatment as they can evade feedback mechanisms that counteract pharmacological inhibition of WT PIK3CA . Mutant selective inhibitors have been discovered that lead to selective degradation of E545K and H1047R over WT 56 , along with recent reports of H1047R selective inhibitors. Our data showing very similar conformational changes in H1047R and G1049R suggest that 1047R/L selective small molecules may also be useful in targeting G1049R/S.…”

Immunomodulatory Properties of PI3K/AKT/mTOR and MAPK/MEK/ERK Inhibition Augment Response to Immune Checkpoint Blockade in Melanoma and Triple-Negative Breast Cancer

“…As these new targeted inhibitors enter clinical trials, they could provide a wider toolbox to design combination treatments with enhanced efficacy, tolerability, and specificity. For instance, GDC-0077 preferentially induces HER2-mediated degradation of mutant PI3Kα, resulting in sustained inhibition of phospho-AKT, despite the release of negative feedback of upregulation in receptor tyrosine kinase signaling [60]. In addition, GDC-0077, compared with other PI3K inhibitors, shows stronger potency against PIK3CAmutant cell lines in vitro and leads to greater tumor regression in PIK3CA-mutant xenograft models [60].…”

“…For instance, GDC-0077 preferentially induces HER2-mediated degradation of mutant PI3Kα, resulting in sustained inhibition of phospho-AKT, despite the release of negative feedback of upregulation in receptor tyrosine kinase signaling [60]. In addition, GDC-0077, compared with other PI3K inhibitors, shows stronger potency against PIK3CAmutant cell lines in vitro and leads to greater tumor regression in PIK3CA-mutant xenograft models [60]. Thus, GDC-0077 may offer exciting opportunities to explore more tolerable and efficacious combinations in melanoma and breast cancer patients harboring PIK3CA mutation [60].…”

In the literature: February 2022

“…Song et al. 3 published in Cancer Discovery an impressive article showing a unique mechanism of action of PI3K inhibitors. The authors demonstrated that taselisib and inavolisib were stronger inducers of cell antiproliferation in PIK3CA- mutant cancer cells than other inhibitors.…”