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

<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>RB1</jats:italic> loss, activating alterations in <jats:italic>AKT1</jats:italic>, <jats:italic>RAS</jats:italic>, <jats:italic>AURKA</jats:italic>, <jats:italic>CCNE2, ERBB2,</jats:italic> and <jats:italic>FGFR2,</jats:italic> and loss of ER expression. <jats:italic>In vitro</jats:italic> experiments confirmed that these alterations conferred CDK4/6i resistance. Cancer cells cultured to resistance with CDK4/6i also acquired <jats:italic>RB1</jats:italic>, <jats:italic>KRAS</jats:italic>, <jats:italic>AURKA</jats:italic>, or <jats:italic>CCNE2</jats:italic> 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.</jats:p><jats:sec><jats:title>Significance</jats:title><jats:p>We 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 precision-based approaches to overcome resistance in many patients with HR+ MBC.</jats:p></jats:sec>

Mechanisms of Sensitivity and Resistance to CDK4/6 Inhibition

“…Acquired alteration in upstream tyrosine kinases likely functions through the activation of the PI3K/AKT and RAS/ERK pathways, and specific aberrations in these transducing pathways have also been associated to resistance to endocrine therapy and CDK4/6 inhibitors. AKT1 and AKT3 mutations and amplifications correlate with resistance to CDK4/6 inhibitors in breast cancer cells (Herrera-Abreu et al, 2016;Jansen et al, 2017;Li et al, 2018;Wander et al, 2019). Alterations in PIK3CA, however, are similarly present in both sensitive and resistant biopsies, suggesting that PI3KCA is unlikely to be a marker of resistance (Wander et al, 2019).…”

“…High CDK4 levels in these tumors actually associates with endocrine resistance which is, however, mitigated by CDK4/6 inhibitors (Finn et al, 2019), and the combination of these Cancer Cell Review CDK4/6 inhibitors with hormonotherapy has become the standard of care in the treatment of metastatic ER + /HER2disease (Table 1). In two recent studies, loss of ER expression and ESR1 mutations were observed more frequently in biopsies resistant to CDK4/6 inhibitors plus anti-estrogens than in sensitive tumors (Li et al, 2018;Wander et al, 2019). However, endocrineresistant tumors maintain sensitivity to CDK4/6 irrespective of ESR1 mutation status (Fribbens et al, 2016), and it is, therefore, not clear to what extent these alterations specifically contributed to resistance to CDK4/6 inhibitors versus hormone therapy in patients receiving combination treatments.…”

“…Accordingly, tumors with increased expression of FGFR2 or ERBB3 display greater PFS in the presence of CDK4/6 inhibitors (Finn et al, 2019). However, amplification or activating alterations in FGFR1/2 and ERBB2 are more frequently in biopsies resistant to CDK4/6 inhibitors and to endocrine therapy (Croessmann et al, 2019;Formisano et al, 2019;Mao et al, 2019;Nayar et al, 2019;Wander et al, 2019) (Figure 2). Although it is not clear how these alterations may induce resistance to CDK4/6 inhibitors, they may either increase the threshold for CDK4/6 inhibition or activate CDK4/6-independent parallel pathways.…”

“…The specific interaction with HER2 in breast cancer is a complex issue that deserves further evaluation. Activation of HER2 correlates with resistance to CDK4/6 inhibitors (Wander et al, 2019) and activation of the CDK4 pathway drives resistance to HER2 inhibitors (Goel et al, 2016). CDK4/6 inhibitors and HER2-directed therapies synergize in genetically modified mouse models (Goel et al, 2016), and new clinical studies suggest no safety concerns and promising activities of abemaciclib--but not ribociclib--in combination with hormonotherapy and trastuzumab, in HER + breast cancer (Goel et al, 2019;Patnaik et al, 2016;Tolaney et al, 2019).…”

A novel sequential treatment of 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 promote cytotoxic effect of CDDP, while overexpression of RB could restore the sensitivity of RB-de cient cells to PD. Some literatures and our study all demonstrated that RB could act as a hallmark to select patients suffered cancer who would be likely to bene t from PD treatment and the loss of RB function may be the main cause of primary and secondary drug resistance [29][30][31].…”