Title:Back to the Bench? MEK and ERK Inhibitors for the Treatment of KRAS Mutant Lung Adenocarcinoma
Volume: 25
Issue: 5
Author(s): Jens Kohler*, Marco Catalano and Chiara Ambrogio*
Affiliation:
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts,United States
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts,United States
Keywords:
KRAS, non-small cell lung cancer, MEK and ERK inhibitors, GEMM, clinical trials, immune checkpoint
blockade.
Abstract: Background: Lung cancer accounts for one in five cancer deaths worldwide and mutations
in the gene encoding for the Kirsten rat sarcoma (KRAS) oncoprotein define the largest molecular
subset of non-small cell lung cancer (NSCLC). These tumors are characterized by activated
MAPK signaling, however, no targeted inhibitors of mutant KRAS or of downstream signaling
molecules have yet been approved for routine clinical use.
Objective: The primary objective of this review is to critically summarize the current developmental
state of MEK and ERK inhibitors in pre-clinical models and in human clinical trials for
KRAS mutant lung cancer particularly in light of the newly emerging concept of immune checkpoint
blockade.
Method: We performed a Pubmed-based literature search and considered publications from the
fields of basic and translational biomedicinal and biochemistry research, as well as from past and
ongoing human clinical trials (www.clinicaltrials.gov).
Results and Conclusions: MAPK pathway targeting agents are efficacious in pre-clinical models
but their benefit is limited for patients with KRAS mutant NSCLC due to the lack of predictive
factors, toxicity and the adaptive dynamic kinome reprogramming within the tumor. Overall,
MEK inhibitors have advanced further in clinical development compared to ERK inhibitors. New
treatment strategies as e.g. immune checkpoint blockade are currently revolutionizing the treatment
paradigms and future clinical trials need to show if they replace MAPK targeting strategies
or are used as add-on.
