Breaking the ERK1/2 negative feedback loop: avoiding reactivation and acquisition of resistance by ERK1/2 to...

The RAS-RAF-MEK-ERK signaling pathway plays a key regulatory role in the survival and proliferation of mammalian cells. Accordingly, deregulated activation of this cascade by a mutated K-RAS (mutK-RAS) is a major cause of cancer initiation and progression. These findings led to the development of synthetic inhibitors that target the mutK-RAS protein, as a therapeutic approach. However, the challenging design of synthetic compounds that effectively and selectively inhibit the mutK-RAS, and the high prevalence of acquired resistance to the mutK-RAS inhibitors, motivated also the development of synthetic inhibitors to downstream effectors of mutK-RAS, such as ERK1/2. Unfortunately, these putative anti-cancer drugs also exhibited limited efficacy, due to the reactivation of the inhibited ERK1/2 kinases by their deregulated upstream activators, RAF and MEK, an effect that led to an acquired resistance. Recently, several studies reported the targeting of novel, mutK-RAS-RAF-MEK-ERK sustaining proteins whose downregulation led to ERK1/2 inhibition, without subsequent ERK1/2 reactivation and without acquired resistance. The knockdown or inhibition of the intracellular tyrosine kinase FER, whose expression level is linked to poor prognosis of cancer patients, led to significant and persistent inhibition of ERK1/2, without subsequent reactivation. In an additional report, myotrophin (MTPN) was identified as a crucial mediator of ERK1/2 oncogenic activation. Accordingly, knockdown of MTPN blocked ERK1/2 activity without inducing later reactivation, or acquired resistance of these kinases. Here, we discuss these novel findings, which could pave the way for novel intervention approaches with deregulated ERK1/2 activation, with significant ramifications for the therapeutic targeting of the key K-RAS-ERK1/2 oncogenic pathway.