Can the Combination of CDK4 and MEK Inhibitors Reduce Resistance to Lung Cancer Therapy?
Posted: Monday, September 13, 2021
Don L. Gibbons, MD, PhD, of The University of Texas MD Anderson Cancer Center, Houston, and colleagues demonstrated that co-administration of CDK4 and MEK inhibitors in multiple in vitro and in vivo models appeared to overcome epithelial-to-mesenchymal transition-mediated tumor heterogeneity and ultimately may prevent the outgrowth of resistant tumor populations better than monotherapies. Published in JCI Insight, these results also identified that the CDK4 and MAPK pathways interact with each other regarding the progression of lung cancer.
Murine lung cancer cell lines 344P and 393P created from KrasLA1/positive/p53R172H genetically engineered mice were infected with pooled small hairpin RNA lentiviral targeting genes correlating with known kinase activity. Cells were either seeded in 96 well plates and treated with various drug concentrations or implanted into 129/Sv mice and allowed to form tumors later to be excised.
It was found that mesenchymal-like cells and their respective tumors were reliant on CDK4 for growth, and mRNA expression of CDK4 demonstrated a positive correlation with 76-gene epithelial-to-mesenchymal transition signatures in 118 human and 41 KRAS-mutant non–small cell lung cancer cell lines. Notably, both cell lines appeared to be more sensitive to CDK4 inhibitors. When cells were treated with the MEK inhibitor selumetinib (AZD6244) or the CDK4 inhibitor palbociclib, single-agent treatment revealed reciprocal pathway activation, and combination therapy suppressed MAPK and CDK4 pathways with enhanced tumor cell killing.
Combining these MEK and CDK4 inhibitors also induced a response in implanted mice. Despite acquiring resistance to single-agent palbociclib, the addition of selumetinib seemed to resensitize these mice and suppressed tumor growth, with a durable response for approximately 10 weeks. In contrast, cells with KRAS mutations alone demonstrated complete regression when treated with selumetinib; cells with p53 and miR-141/200c deletions had better tumor growth control with palbociclib than with selumetinib. Notably, the combination of these agents yielded a more significant tumor reduction across all three genotypes.
Disclosure: For full disclosures of the study authors, visit insight.jci.org.