Abstract
Palbociclib, a CDK4/6 inhibitor, has been granted accelerated approval by US FDA for hormone receptor-positive HER2-negative metastatic breast cancer. To determine potential biomarkers of palbociclib sensitivity to assist in patient selection and clinical development, we investigated the effects of palbociclib in a panel of molecularly characterized breast cancer cell lines. We quantified palbociclib sensitivity and c-myc expression in 11 breast cancer cell lines, 124 breast cancer samples, and The Cancer Genome Atlas database. We found non-TNBC subtypes were more sensitive to palbociclib than TNBC. Activation of c-myc led to differential palbociclib sensitivities, and further inhibition of c-myc enhanced palbociclib sensitivity. Moreover, we identified for the first time a c-myc/miR-29b-3p/CDK6 axis in breast cancer that could be responsible for c-myc-induced palbociclib insensitivity, in which c-myc activation resulted in downregulation of miR-29b-3p, further activated CDK6 and inhibited cell-cycle arrest at G1 phase. Moreover, downregulated (inactived) c-myc-induced oncogenic addiction could increase palbociclib efficacy, using both Xenograft model and patient-derived tumor xenograft (PDTX) model. Our finding extends the concept of combined blockade of the CDK4/6 and c-myc signaling pathways to increase palbociclib sensitivity, making c-myc a promising biomarker for palbociclib sensitivity in breast cancer.
Highlights
Breast cancer is the most common malignancy, the second most common cause of cancer deaths among women[1]
A panel of 11 human breast cancer cell lines representing of luminal, HER2-positive breast cancer, or triple-negative breast cancer (TNBC) were treated with Palbociclib
Given that palbociclib blocks cell cycle at G1/S phase, we focused on genes that could critically implicate in the G1/ S transition
Summary
Breast cancer is the most common malignancy, the second most common cause of cancer deaths among women[1]. Great advances have been made in the understanding of this malignancy, and several molecular characteristics of breast cancer have been identified[2,3]. Such a molecular understanding has paved the way for the treatment of breast cancer by targeting specific pathogenic molecular alterations. The trials, known as PALOMA-1 and PALOMA-2, compared palbociclib plus letrozole with letrozole alone in patients who had not Official journal of the Cell Death Differentiation Association
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