Cyclin D1 expression as a potential prognostic factor in advanced KRAS-mutant non-small cell lung cancer

Abstract

Background: East Asian, including Thailand, lung cancer population may have a relatively lower prevalence of KRAS mutations than Caucasians. We investigated the prevalence and clinical characteristics of KRAS-driven non-small cell lung cancer (NSCLC) patients and the expression of cyclin D1, one of the KRAS downstream targets.Methods: Lung cancer patients who received treatment at the King Chulalongkorn Memorial Hospital between January 2015 and July 2017 were enrolled. We identified KRAS mutations using allele specific PCR KRAS mutation testing. Cyclin D1 expression was determined using immunohistochemistry.Results: After excluding 376 EGFR mutations and inadequate samples, we enrolled 95 patients eligible for KRAS mutation testing. KRAS mutations were identified in 28 out of 95 patients. There were 26 patients with KRAS codon 12/13 and 2 patients with KRAS codon 61 mutations. The prevalence of KRAS mutations among informative samples was 28 out of 357 (7.8%) which was relatively lower than that reported in Caucasian population. Smoking and male were significantly associated with KRAS mutations. The prognosis of KRAS-mutant NSCLC patients in particular codon 61 mutations was worse than that found in KRAS-and EGFR-wild-type (KRAS WT/EGFR WT) NSCLC patients (P=0.048). The levels of cyclin D1 expression in KRAS-mutant NSCLC were significantly higher than those in KRAS WT/EGFR WT NSCLC (P=0.02).A better prognosis of KRAS-mutant NSCLC patients with low cyclin D1 expression was observed when compared with those with high cyclin D1 expression (median overall survival 41.7 vs. 3.5 months, P=0.037). Conclusions:We found a moderate prevalence of KRAS mutations in lung cancer in Thailand. Clinical characteristics were similar to those of Caucasian population. Most KRAS-mutant NSCLC had high cyclin D1 expression. Cyclin D1 expression may serve as a useful prognostic biomarker in KRAS-mutant lung cancer. Validation of this finding in larger cohort is required.

<p>Inhibition of ERKs/Akt-Mediated c-Fos Expression Is Required for Piperlongumine-Induced Cyclin D1 Downregulation and Tumor Suppression in Colorectal Cancer Cells</p>

“…Given the crucial role of Cyclin D1 for cell cycle regulation, it's not surprising that Cyclin D1 is overexpressed in human cancers. 8 Previous studies revealed that highly expressed Cyclin D1 promoted tumor cell growth and correlated with poor prognosis in human lung cancer, 9 colorectal cancer, 10 gastric cancer, 11 and liver cancer. 12 The expression of Cyclin D1 is tightly regulated at multiple levels, including transcriptional, translational, and posttranslational.…”

Assessment of Resistance Mechanisms and Clinical Implications in Patients with KRAS Mutated-Metastatic Breast Cancer and Resistance to CDK4/6 Inhibitors

“…Several studies have suggested that a mutant KRAS protein may induce cyclin D1 overexpression through the constitutive activation of the RAS-MEK-ERK pathway, resulting in cell growth and cancer development [13]. Luangdilok et al (in 2019) showed that a downstream effector of KRAS is Cyclin D1/CCND1, which seems to control cell division by regulating CDK4/6 activity during the G1-S transition of the cell cycle [14,15]. Nevertheless, no previous studies have been conducted to evaluate the potential predictive role of KRAS status on the emergence of resistance to CDK4/6i.…”

Synergistic effects of piperlongumine and gemcitabine against KRAS mutant lung cancer

“…2 The prevalence of KRAS mutation is relatively high in the Caucasian population when compared with Asian ethnicity. 2,3 Autophagy is involved in regulation of cell growth, lipid metabolism, and mitochondrial function of KRASdriven lung cancer cells. 4 Microtubule-associated protein 1 light chain 3B (LC3B) is essential for autophagosome development and therefore is used to monitor autophagic activity.…”