Title:Modulation of Sensitivity to Antitumor Agents by Targeting the MAPK Survival Pathway
Volume: 19
Issue: 5
Author(s): Giacomo Cossa, Laura Gatti, Giuliana Cassinelli, Cinzia Lanzi, Nadia Zaffaroni and Paola Perego
Affiliation:
Keywords:
BRAF, cisplatin, combination treatment, cytotoxic agents, ERK1/2, MAPK, MEK, target-specific agents, antitumor agents, DNA damage
Abstract: Mitogen-activated protein kinases (MAPK) are involved in a complex network which regulates a variety of cellular processes
including proliferation, survival and death. The molecular characterization of the pathway has shown aberrant activation in several human
tumors, due to the deregulation of receptor tyrosine kinases or to mutations of pathway components. Progress in understanding the
MAPK network has led to the development of target-specific agents in clinical trials. The relevance of MAPK in response and resistance
to antitumor agents has been recognized, although the outcome of MAPK activation can vary depending on the molecular background of
tumor cells and on the type of activated kinase. The canonical cascade of MAPK, i.e., depending on the Extracellular Signal-Regulated
Kinases (ERK), can act in protective signalling pathways, thereby limiting DNA damage. Since tumor cell survival can be sustained by
ERK and cross talk of ERK with other pathways, modulation of sensitivity to antitumor agents by targeting the ERK cascade appears to
be an amenable approach. Indeed, ERK play a role in resistance to both cytotoxic and target-specific agents. Preclinical studies support
the relevance of drug combination approaches to enhance the efficacy of antitumor treatments. Combinations of pharmacological inhibitors
of the ERK cascade and conventional or target-specific antitumor agents may be helpful in an attempt to overcome drug resistance. A
deeper understanding of the genetic alterations of tumor cells and of tumor heterogeneity as well as of drug resistance mechanisms is expected
to contribute to the rational design of MAPK-mediated drug combinations that will lead to reversal of drug resistance.
