The Genomic Landscape of Intrinsic and Acquired Resistance to Cyclin-Dependent Kinase 4/6 Inhibitors in Patients with Hormone Receptor–Positive Metastatic Breast Cancer

Abstract

Clinical resistance mechanisms to CDK4/6 inhibitors in HR+ breast cancer have not been clearly defined. Whole exome sequencing of 59 tumors with CDK4/6i exposure revealed multiple candidate resistance mechanisms including RB1 loss, activating alterations in AKT1, RAS, AURKA, CCNE2, ERBB2, and FGFR2, and loss of ER expression. In vitro experiments confirmed that these alterations conferred CDK4/6i resistance. Cancer cells cultured to resistance with CDK4/6i also acquired RB1, KRAS, AURKA, or CCNE2 alterations, which conferred sensitivity to AURKA, ERK, or CHEK1 inhibition. Besides inactivation of RB1, which accounts for ~5% of resistance, seven of these mechanisms have not been previously identified as clinical mediators of resistance to CDK4/6 inhibitors in patients. Three of these-RAS activation, AKT activation, and AURKA activation-have not to our knowledge been previously demonstrated preclinically. Together, these eight mechanisms were present in 80% of resistant tumors profiled and may define therapeutic opportunities in patients. SignificanceWe identified eight distinct mechanisms of resistance to CDK4/6 inhibitors present in 80% of resistant tumors profiled. Most of these have a therapeutic strategy to overcome or prevent resistance in these tumors. Taken together, these findings have critical implications related to the potential utility of precisionbased approaches to overcome resistance in many patients with HR+ MBC..

Novel sequential treatment with palbociclib enhances the effect of cisplatin in RB-proficient triple-negative breast cancer

“…In RB-knockdown or RB-deficient cell lines, PD could not induce cell cycle arrest, and PD-CDDP could not enhance the cytotoxic effect of CDDP, but the overexpression of RB restored the sensitivity of RB-deficient cells to PD. Some studies and our study have demonstrated that RB can act as a marker to select patients suffering from cancer who are likely to benefit from PD treatment, and the loss of RB function may be the main cause of primary and secondary drug resistance to PD [ 29 – 31 ].…”

Novel sequential treatment with palbociclib enhances the effect of cisplatin in RB-proficient triple-negative breast cancer

“…In RB-knockdown or RB-de cient cell lines, PD could not induce cell cycle arrest, and PD-CDDP could not enhance the cytotoxic effect of CDDP, but the overexpression of RB restored the sensitivity of RB-de cient cells to PD. Some studies and our study have demonstrated that RB can act as a marker to select patients suffering from cancer who are likely to bene t from PD treatment, and the loss of RB function may be the main cause of primary and secondary drug resistance to PD [29][30][31].…”

In the literature: August 2020

“…Wander et al published in Cancer Discovery an article that performed the genomic landscape of resistance to CDK4/6i via whole exome sequencing of metastatic tumour biopsies. 7 To identify potential mechanisms of resistance, they analysed 59 samples that reflected sensitivity, intrinsic resistance and acquired resistance. They identified eight specific categories of alterations that were enriched in the resistant tumours: biallelic disruption of RB1, activating mutations and/or amplification of AKT1, activating mutations in KRAS/HRAS/NRAS, activating mutations and/or amplification of FGFR2, activating mutations in ERBB2, amplifications of CCNE2, amplification of AURKA and loss of ER (assessed by immunohistochemistry).…”