Retinoblastoma Expression and Targeting by CDK4/6 Inhibitors in Small Cell Lung Cancer

Abstract

The canonical model of “small cell lung cancer” (SCLC) depicts tumors arising from dual inactivation of TP53 and RB1. However, many genomic studies have persistently identified tumors with no RB1 mutations. Here, we examined RB1 protein expression and function in SCLC. RB1 expression was examined by immunohistochemical analysis of 62 human SCLC tumors. These studies showed that ~14% of SCLC tumors expressed abundant RB1 protein, which is associated with neuroendocrine (NE) gene expression and is enriched in YAP1 expression, but no other lineage proteins that stratify SCLC. SCLC cells and xenograft tumors with RB1 protein expression were sensitive to growth inhibition by the CDK4/6 inhibitor palbociclib, and this inhibition was shown to be dependent on RB1 expression by CRISPR knockout. Furthermore, a patient with biopsy-validated wt RB1 SCLC who received the CDK4/6 inhibitor abemaciclib demonstrated a dramatic decrease in mutant TP53 ctDNA allelic fraction from 62.1% to 0.4% and decreased tumor mass on CT scans. Importantly, immunohistochemistry of the diagnostic biopsy specimen showed RB1 positivity. Finally, we identified a transcriptomics-based RB1 loss-of-function signature that discriminates between SCLC cells with or without RB1 protein expression and validated it in the patient who was responsive to abemaciclib, suggesting its potential use to predict CDK4/6 inhibitor response in SCLC patients. Our study demonstrates that RB1 protein is an actionable target in a subgroup of SCLC, a cancer that exhibits no currently targetable mutations.

De Novo SCLC Transformation From KRAS G12C-Mutated Lung Adenocarcinoma With Excellent Response to Sotorasib: A Case Report

“… 8 , 9 , 10 Although many cases of conversion from positive in adenocarcinoma to negative in SCLC have been reported in resistant cases post-TKIs, 11 there was no case wherein both were positive. Positivity of RB in IHC indicates a functional RB pathway, 12 and our results strongly support the concept that both tumor components of de novo SCLC and adenocarcinoma share a common histologic origin. Because this is the first case in which IHC for both adenocarcinoma and SCLC with KRAS mutation was performed, further cases are needed to determine whether it is specific to this case.…”

Molecular and Pathologic Characterization of YAP1-Expressing Small Cell Lung Cancer Cell Lines Leads to Reclassification as SMARCA4-Deficient Malignancies

“… 46 ) have all demonstrated anticancer activity in SMARCA4-deficient SCLC-Y cell lines. Furthermore, findings from preclinical studies employing these SMARCA4-deficient SCLC-Y cell lines have been used as a basis to initiate clinical trials in SCLC, highlighting the clinical importance of resolving the identity of these tumors ( 47, 48 ). In contrast to SCLC, emerging evidence suggests that SMARCA4-UT may respond poorly to chemotherapy ( 49, 50 ).…”

DNA damage induced by CDK4 and CDK6 blockade triggers anti-tumor immune responses through cGAS-STING pathway

“…More importantly, we have provided evidence that this CDK4/6-deficient triggered pathway plays an important role in enhancing anti-tumor immunity by CDK4/6 inhibitors. To study the role of CDK4 and CDK6 in tumor cells, it is important to evaluate Rb status as loss of RB leads to resistance of CDK4/6 inhibitors 33 , 38 . We detected that RB was expressed in WT cells and the phosphorylation of RB was decreased in Cdk4 and Cdk6 knockout cells, demonstrating that RB1 is functional in MCA205.…”