Geoffrey I. Shapiro, MD, PhD
Although the roles of cyclin-dependent kinases (CDKs) were established more than 20 years ago, early anticancer inhibitors in the class resulted in high toxicity levels. Now, a new generation of more selective inhibitors of CDK4 and CDK6 has entered the clinic in combination therapies for patients with breast cancer.
These agents also are being investigated in patients with KRAS
-mutant malignancies. Early-stage results have been promising, but hopes for an advance in KRAS
-mutant non–small cell lung cancer (NSCLC) were dampened recently when the phase III JUNIPER study evaluating abemaciclib (Verzenio) in this population failed to meet its primary endpoint.
There is a pressing need for new therapeutic strategies that target KRAS
, the Kirsten rat sarcoma viral oncogene homolog, one of the most frequently mutated genes in human cancers. “Despite some recent advances, mutant KRAS
remains a very challenging target,” said Pier Paolo Scaglioni, MD, an associate professor at UT Southwestern Medical Center and a member of the Harold C. Simmons Comprehensive Cancer Center, both in Dallas, Texas. “There is a dearth of treatment options for tumors initiated by this gene.”1
CDKs and KRAS
signaling are both players in oncogenic events (Figure
CDK4/6 phosphorylates the retinoblastoma tumor suppressor protein through interaction with D-type cyclins, leading to G1
to S phase cell-cycle progression. CDK4 and CDK6 activity is regulated by the INK4 family, and the INK4- CDK4/CDK6-cyclin D axis is frequently genetically or epigenetically disrupted in cancer, leading to increased kinase activity. Furthermore, increased CDK4 or CDK6 activity has led to suppressed senescence, contributing to the initiation and maintenance of transformed cells.
Figure. Relationship of KRAS Signaling to CDKs2
Mutations in KRAS
are among the earliest and most important drivers of disease progression. When KRAS
is mutated, several downstream pathways, such as the MEK/ ERK and PI3K/AKT signaling pathways, become constitutively activated.
mutations contribute to approximately 20% of human tumors. Most KRAS
mutations are point substitutions in codons 12 and 13 and have been shown to be negative predictors of response to antiEGFR antibodies. KRAS
mutations are detected through quantitative polymerase chain reaction (PCR)-based methods. Frequently used methods include allele-specific PCR, real-time PCR with melt-curve analysis, and nucleic acid sequencing (pyrosequencing and dideoxy sequencing). Recent studies have also investigated the detection of circulating tumor cells in peripheral blood, concluding that KRAS
mutations were identified in a similar percentage of blood samples compared with tumor tissue. Samples with at least 5% presence of the non–wild-type band have been considered KRAS
mutations are found in about 30% of lung adenocarcinomas, corresponding with a worse prognosis compared with patients having KRAS
wild-type tumors. Persistent activation of RAS signaling results from these mutations, contributing to uncontrolled growth and eventually, malignant transformation.
In KRAS-induced lung adenocarcinoma models, CDK4 activity is needed for tumor progression. CDK4 and RAS co-expression induces phosphorylation of the retinoblastoma protein, which leads to invasive neoplasms. Importantly, ablation of CDK4 leads to selective senescence of cells expressing KRAS, suggesting that CDK4 may be a worthy drug candidate for patients with KRAS
-mutated non–small cell lung cancer (NSCLC).
mutations have been reported in approximately 50% of colorectal cancers (CRCs), which lead to constitutive activation of the RAF/ MEK/ERK signaling pathway. These mutations are proven predictive biomarkers of resistance to antiEGFR therapy. Patients with KRAS mutations have fewer options for effective therapies, and currently, no therapies successfully exploit KRAS
mutations to target malignant cells.