Identification of resistance mechanisms to PI3K alpha inhibition in breast cancer

Activating mutations in PIK3CA occur in 20-40% of all breast cancer patients. Metastatic HR-positive/ HER2 negative breast cancer patients with PIK3CA can nowadays be treated with alpelisib, a phosphoinositide 3-kinases (PI3K) α selective inhibitor. However, as with many other targeted therapies, resistance mechanisms to targeted therapies are frequent and evolve through a variety of mechanisms. Unraveling the mechanisms by which cancer cells resist therapy, finding better biomarkers for patient stratification, and effective combinatorial treatments are highly warranted for improving the long-term clinical remission of breast cancer patients.
Cancer cells can be intrinsically resistant or acquire resistance through adaptive responses. One possibility for the emergence of resistance (intrinsic or acquired) is the accumulation of mutations that ultimately result in loss of drug-to-target interactions, enhanced bypass signaling, enhanced downstream signaling, altered cellular metabolism, the elevation of other epigenetic adaption processes, or reduced interaction with the immune system.
In my Ph.D. project, I investigated genetic alterations conferring resistance to PI3Kα inhibition. For this purpose, we used a genome-wide PiggyBac transposon-mediated mutagenesis screen in a PIK3CAH1047R mutated murine tumor model and combined these results with an unbiased transcriptional profiling of PI3Kα resistant tumors in a similar preclinical model. We discovered that the tumor suppressor Nf1 was frequently lost in tumors resistant to PI3Kα inhibition and confirmed that NF1 loss increases resistance to PI3Kα inhibition in human cell lines and patient-derived organoids. Moreover, we show that co-treatment with N-acetyl-cysteine (NAC) sensitizes cancer cells with NF1 loss to PI3Kα inhibition. Our findings highlight the usefulness of mutational screens for investigating resistance mechanisms to targeted therapies. Notably, we propose that loss of NF1 could serve as a predictive biomarker for patients treated with PI3Kα inhibitors and that such patients could benefit from co-treatment with NAC, a well-tolerated food supplement.