Comparison of <i>PIK3CA</i> Mutation Prevalence in Breast Cancer Across Predicted Ancestry Populations

Chen, Jessica W.; Murugesan, Karthikeyan; Newberg, Justin Y.; Sokol, Ethan S.; Savage, Heidi; Stout, Thomas J.; Maund, Sophia L.; Hutchinson, Katherine E.

doi:10.1200/po.22.00341

Cited by 9 publications

(1 citation statement)

References 73 publications

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“…Dysregulation of the PI3K/AKT/mTOR pathway is common in ER-dependent breast cancer, and activating mutations of PIK3CA , the catalytic subunit of class 1 PI3 Kinase, occur in 40% of these tumors 8 . The PI3K pathway enhances the proliferation, motility and invasiveness of these tumor cells and activation of the mTOR complex 1 (mTORC1) maintains high levels of eIF4E-dependent protein translation 9,10 11–14 .…”

Section: Introductionmentioning

confidence: 99%

eIF4A controls translation of estrogen receptor alpha and is a therapeutic target in advanced breast cancer

Boyer,

Sharma,

Dorso

et al. 2024

Preprint

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The majority of human breast cancers are dependent on hormone stimulated estrogen receptor alpha (ER) and are sensitive to its inhibition. Treatment resistance arises in most advanced cancers due to genetic alterations that promote ligand independent activation of ER itself or ER target genes. Whereas re-targeting of the ER ligand binding domain (LBD) with newer ER antagonists can work in some cases, these drugs are largely ineffective in many genetic backgrounds including ER fusions that lose the LBD or in cancers that hyperactivate ER targets. By identifying the mechanism of ER translation, we herein present an alternative strategy to target ER and difficult to treat ER variants. We find that ER translation is cap independent and mTOR inhibitor insensitive, but dependent on 5'UTR elements and sensitive to pharmacologic inhibition of the translation initiation factor eIF4A, an mRNA helicase. EIF4A inhibition rapidly reduces expression of ER and short lived targets of ER such as cyclin D1 and other components of the cyclin D CDK complex in breast cancer cells. These effects translate into suppression of growth of a variety of ligand independent breast cancer models including those driven by ER fusion proteins that lack the ligand binding site. The efficacy of eIF4A inhibition is enhanced when it is combined with fulvestrant, an ER degrader. Concomitant inhibition of ER synthesis and induction of its degradation causes synergistic and durable inhibition of ER expression and tumor growth. The clinical importance of these findings is confirmed by results of an early clinical trial (NCT04092673) of the selective eIF4A inhibitor zotatifin in patients with estrogen receptor positive metastatic breast cancer. Multiple clinical responses have been observed on combination therapy including durable regressions. These data suggest that eIF4A inhibition could be a useful new strategy for treating advanced ER+ breast cancer.

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