Issues
-
Cover Image
Cover Image
PIK3CA, encoding PI3Kα, is commonly mutated across human cancers, including in approximately 40% of hormone receptor (HR)–positive breast cancer. Orthosteric PI3Kα inhibitors that bind the PI3Kα active site like alpelisib, which has been approved by the FDA in combination with the estrogen receptor antagonist fulvestrant for HR-positive breast cancer, are not mutant selective and cause dose-limiting hyperglycemia and subsequent hyperinsulinemia due to inhibition of wild-type PI3Kα. Varkaris and colleagues (see page 240) used molecular dynamics, cryo-electron microscopy, and DNA-encoded libraries to develop RLY-2608, an allosteric mutant-selective inhibitor of PI3Kα that inhibited tumor growth in PIK3CA-mutant models without causing hyperinsulinemia and led to objective responses in patients with advanced HR-positive, PIK3CA-mutant breast cancer without wild-type PI3Kα-related toxicities. In a second study, Varkaris, de la Cruz, Martin, and colleagues (page 227) profiled 39 patients with advanced HR-positive breast cancer whose tumors acquired resistance to orthosteric PI3Kα inhibitors and observed that 50% of patients had acquired genomic alterations affecting the PI3K pathway, including secondary PIK3CA mutations within the catalytic pocket that were found to decrease orthosteric PI3Kα inhibitor activity. Because RLY-2608 binds to a distinct allosteric pocket on mutant PI3Kα, it retained activity in PIK3CA-mutant tumor cells with secondary PIK3CA mutations, suggesting next-generation allosteric PI3Kα inhibitors could overcome resistance to orthosteric PI3Kα inhibitors. - PDF Icon PDF LinkTable of Contents
- PDF Icon PDF LinkEditorial Board
In This Issue
In the Spotlight
Review
Research Brief
Allosteric PI3Kα Inhibition Overcomes On-target Resistance to Orthosteric Inhibitors Mediated by Secondary PIK3CA Mutations
Analyses of patients with advanced breast cancer resistant to orthosteric PI3Kα inhibitors revealed that secondary resistance mutations in PIK3CA alter the inhibitor binding pocket, which can be overcome by use of the allosteric PI3Kα inhibitor RLY-2608.
Research Articles
Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia
The most prevalent oncogenic mutants of PIK3CA can be selectively targeted by RLY-2608, providing a clinical opportunity to overcome toxicities associated with current treatments.
Combined Immunotherapy Improves Outcome for Replication-Repair-Deficient (RRD) High-Grade Glioma Failing Anti–PD-1 Monotherapy: A Report from the International RRD Consortium
Continuous and obligatory mutagenesis in patients with germline DNA replication-repair deficient refractory glioblastoma allows for sustained immune-surveillance and prolonged survival following synergistic immune-directed combinations.
ESR1 F404 Mutations and Acquired Resistance to Fulvestrant in ESR1-Mutant Breast Cancer
As part of Cohort A of the plasmaMATCH trial, baseline ESR1 mutations were found to be predictive of response to fulvestrant, and ESR1 F404 mutations that occur in cis with classical activating ESR1 mutations promote resistance.
NKG2A Is a Therapeutic Vulnerability in Immunotherapy Resistant MHC-I Heterogeneous Triple-Negative Breast Cancer
MHC-I heterogeneity drives anti-PD-L1 resistance in triple negative breast cancer tumors and enhances NK cell infiltration, and combination of anti-PD-L1 therapy with anti-NKGA2A, which suppresses NK cell function, restores response.
Alveolar Differentiation Drives Resistance to KRAS Inhibition in Lung Adenocarcinoma
Targeting KRAS in lung cancer cells promotes differentiation into a KRAS inhibitor-resistant cell state with alveolar identity, which represents a novel target for overcoming resistance to KRAS inhibition.
Receptor-interacting Protein Kinase 2 Is an Immunotherapy Target in Pancreatic Cancer
Genetic depletion or small molecule inhibition of RIPK2-sensitized pancreatic ductal adenocarcinoma to anti-PD-1 therapy via an increase in MHC-I surface levels by negating NBR1-mediated autophagy-lysosomal degradation.
Tumor Explants Elucidate a Cascade of Paracrine SHH, WNT, and VEGF Signals Driving Pancreatic Cancer Angiosuppression
Pancreatic ductal adenocarcinoma explant models reveal that malignant epithelial cells induce Hedgehog signaling in fibroblasts that leads to inhibition of noncanonical WNT signaling and VEGFR2-dependent endothelial hypersprouting.
Loss-of-Function but Not Gain-of-Function Properties of Mutant TP53 Are Critical for the Proliferation, Survival, and Metastasis of a Broad Range of Cancer Cells
Evaluation of a large panel of human cancer cells revealed that gain-of-function effects of mutant TP53 are not required for tumor growth and therapy resistance, whereas loss of wild-type TP53 functions is essential for these phenotypes.
Advertisement
Email alerts
NOTICE: This notice serves to inform the reader that, in 2023, AACR received a donation by Pfizer of the rights to royalties from the sale—within the United States—of Bavencio® (avelumab), a pharmaceutical owned by Merck. None of these funds are being, or will be, used to directly support any specific publication or author. If an individual article is published that deals with this particular drug, such article will include standard financial disclosures per AACR journal policy. For more detail regarding AACR’s established policies for authors, please go to https://aacrjournals.org/pages/editorial-policies#coi.
RSS Feeds