Oncogenic KRAS-associated gene signature defines co-targeting of CDK4/6 and MEK as a viable therapeutic strategy in colorectal cancer

Abstract

Therapeutic strategies against KRAS mutant colorectal cancers are developed using cell line models, which do not accurately represent the transcriptome driven by oncogenic KRAS in tumors. We sought to identify a KRAS-associated gene signature from colorectal tumors to develop a precise treatment strategy. Integrative analysis of quantitative KRAS mutation detection and matched gene expression profiling in 55 CRC bulk tumors was carried out to define a gene signature enriched in CRC tumors with high KRAS mutation. The KRAS-associated gene signature identified exhibits functional enrichment in cell cycle and mitosis processes, and includes mitotic transcription factor, FOXM1. Combination treatment of CDK4/6 inhibitor Palbociclib and MEK inhibitor PD0325901 was tested in KRAS-mutant, BRAF-mutant CRC, normal colon epithelial lines and xenografts models to determine their efficacy and toxicity and to monitor the changes in the gene signature. Inhibiting CDK4/6, an upstream regulator of FOXM1, and MEK synergistically depleted FOXM1 and KRAS-associated gene signature, suggesting that CDK4/6 and MEK regulate the KRAS gene signature. The combined inhibition of CDK4/6 and MEK elicited a robust therapeutic response in KRAS-dependent and BRAF-mutant CRC, both in vitro and in vivo and this correlated with downregulation of the KRAS-associated gene signature. Our preclinical study demonstrated the efficacy of Palbociclib and PD0325901 combinatorial treatment selectively in KRAS-dependent and BRAF-mutant CRC but not in normal colon epithelial cells. The KRAS-associated gene signature could facilitate the identification of responsive metastatic CRC to this therapeutic strategy in clinical settings.

Identification of Prognostic Biomarker Signatures and Candidate Drugs in Colorectal Cancer: Insights from Systems Biology Analysis

“…CD44 plays diverse roles in cancer cells [51]; the CDK4 is the target for different cancer treatment including colorectal cancer [51,52]; CENPA is associated in pathobiology of CRC [53]; CENPH was also implicated in CRC [54]; RFC2 is implicated in hematologic cancers [55,56]; MYC is dysregulated in CRC [57][58][59]. CENPN is a protein that in humans is involved in cell cycle process showing direct binding of CENPN to CENPA [60].…”

Development of small-molecule therapeutics and strategies for targeting RAF kinase in BRAF-mutant colorectal cancer

“…In the last 5 years, BRAFm CRC treatment has exhibited breakthrough progress, with increasing novel options moving directly from the bench to the bedside. Novel adaptive signaling mechanisms underlying resistance to BRAF inhibition in BRAFm CRC were discovered, such as the observation that the Wnt/β-catenin pathway 82 and CDK4/6 83 were co-regulated when using a BRAF inhibitor ( Figure 3B ); additionally, other strategies combining a BRAF inhibitor (LGX818) with a Wnt-pathway inhibitor (WNT974) or a CDK4/6 inhibitor (LEE011) were in Phase I or II trials. Additionally, various MEK mutations were identified that diminish sensitivity to both single-agent RAF inhibitors and combined BRAF and MEK inhibition.…”

DNA methylation‐regulated and tumor‐suppressive roles of miR‐487b in colorectal cancer via targeting MYC, SUZ12, and KRAS

“…SUZ12 inhibits the levels of p16 and p21 via an H3K27me3‐mediated suppressive effect, ultimately launching CRC cell proliferation . KRAS‐associated genes exhibit functional enrichment in cell cycle and mitosis, and CDK4/6 inhibition is an effectively therapeutic response in KRAS‐dependent CRC . Because of this paradox, further investigations are still needed to clarify whether a negative feedback loop exists or if other cell cycle enhancement‐related genes are activated to block the miR‐487b‐mediated CRC cell cycle arrest.…”