Abstract
Aberrant activity of oncogenic rat sarcoma virus (RAS) protein promotes tumor growth and progression. RAS-driven cancers comprise more than 30% of all human cancers and are refractory to frontline treatment strategies. Since direct targeting of RAS has proven challenging, efforts have been centered on the exploration of inhibitors for RAS downstream effector kinases. Two major RAS downstream signaling pathways, including the Raf/MEK/Erk cascade and the phosphatidylinositol-3-kinase (PI3K) pathway, have become compelling targets for RAS-driven cancer therapy. However, the main drawback in the blockade of a single RAS effector is the multiple levels of crosstalk and compensatory mechanisms between these two pathways that contribute to drug resistance against monotherapies. A growing body of evidence reveals that the sequential or synergistic inhibition of multiple RAS effectors is a more convenient route for the efficacy of cancer therapy. Herein, we revisit the recent developments and discuss the most promising modalities targeting canonical RAS downstream effectors for the treatment of RAS-driven cancers.
Highlights
SRC (SRC Proto-Oncogene, Non-Receptor Tyrosine Kinase) as one of major MAPKs regulatory protein tyrosine kinases, inhibited the growth of NRAS-mutant melanoma cells and achieved tumor regression in patient-derived xenografts that are resistant to B-Raf inhibitors. These findings suggested that they could provide clinical benefit in melanoma patients with NRAS mutations as a first-line therapy and in relapsed patients as a secondline therapy [65]
IGF1R inhibitor [15] and PI3K inhibitor [14] in lung cancer cells and in vivo models. These results showed that inhibiting the PI3K-mammalian target of rapamycin (mTOR) pathway would potentiate the effectiveness of KRASG12C covalent inhibitors and provide a therapeutic opportunity for patients with
Tremendous progress has been made in understanding the genetic architecture, the biological heterogeneity and the distinct molecular pathways driven by rat sarcoma virus (RAS) oncogenes
Summary
RAS Downstream Effectors for RAS-Driven Cancer Therapy. Rat sarcoma virus (RAS) is involved in distinct cellular processes, including cell division, proliferation, migration and cellular differentiation. Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations These sites lead to the expression of constitutively active RAS proteins that induce cellular transformation and tumorigenesis [4,5]. Except for these mutations, abnormal activity of RAS can arise from GDP-GTP deregulation, loss of GAPs or RTK-mediated activity of GEFs. In the last three decades, tremendous efforts have been expended on targeting RASdriven tumors. Cancer cells develop dependencies upon inhibition of only RAS or a single RAS effector, which contribute to acquired drug resistance in single-agent therapies. We revisit the recent strategies and discuss the most promising approaches targeting canonical RAS downstream effectors for the treatment of RAS-induced cancers
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