The importance of Ras in drug resistance in cancer

Abstract

In this review, we analyse the impact of oncogenic Ras mutations in mediating cancer drug resistance and the progress made in the abrogation of this resistance, through pharmacological targeting. At a physiological level, Ras is implicated in many cellular proliferation and survival pathways. However, mutations within this small GTPase can be responsible for the initiation of cancer, therapeutic resistance and failure, and ultimately disease relapse. Often termed “undruggable,” Ras is notoriously difficult to target directly, due to its structure and intrinsic activity. Thus, Ras‐mediated drug resistance remains a considerable pharmacological problem. However, with advances in both analytical techniques and novel drug classes, the therapeutic landscape against Ras is changing. Allele‐specific, direct Ras‐targeting agents have reached clinical trials for the first time, indicating there may, at last, be hope of targeting such an elusive but significant protein for better more effective cancer therapy. LINKED ARTICLES This article is part of a themed issue on New avenues in cancer prevention and treatment (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.12/issuetoc

Combinatorial Strategies to Target Molecular and Signaling Pathways to Disarm Cancer Stem Cells

“…The combinatorial strategies herein reported foresee the targeting of developmental and oncogenic signaling pathways that are key players in defining several features of CSCs biology, including self-renewal, stemness, EMT, CSCs dormancy, as well as drug resistance, radio-resistance, tumor initiation and dedifferentiation, widely discussed in many published reviews (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28).…”

“…Developmental signaling pathways [including Wnt, Sonic Hedgehog (Shh) and Notch] and oncogenic cascades (including transforming growth factor-beta (TGF-b), Janus kinase/signal transducer and activator of transcription 3 (JAK/ STAT3), phosphatidylinositol 3-kinase/V-Akt murine thymoma viral oncogene/mammalian target of rapamycin (PI3K/AKT/ mTOR), Mitogen-activated protein kinase (MAPK) and V-SRC avian sarcoma (Src) have been identified as key players both in CSCs biology maintenance and in cancer therapy resistance (17,18). The description of these signaling pathways and their roles in defining the biology of CSCs will not be tackled herein and the reader is invited to refer to reviews that widely discuss these topics (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). Although several targeted approaches relying on monotherapy have been developed to affect these pathways, they have shown limited efficacy due to the activation of bypass pathway(s) and to the complexity of signaling networks containing feedback loops and cross-talk.…”

The Importance of Being PI3K in the RAS Signaling Network

“…Although the specific contribution of Ras in the activation of PI3K/AKT leading to therapy resistance is not always addressed, in some cases it is known to play a relevant role [ 249 ]. For example, in lung carcinoma cell lines A549 and H460, targeting EGFR, PI3K [ 250 ], and AKT [ 244 ] enhances repair of DNA-DSBs and induces DNA-PKcs–dependent radiosensitization.…”

Oncogenic KRAS: Signaling and Drug Resistance

“…Acquired resistance occurs for several reasons. Pre-existing and de novo mutations provide chemoresistance and acquired resistance [ 40 ]. Resistance mechanisms happen in a very rare subpopulation of cells, such as cancer stem cells [ 41 , 42 ].…”

“…Upstream RAS-mediated pathways have a common mechanism of resistance to tyrosine kinase inhibitors (TKIs) such as those targeting RTKs, including EGFR and FMS-like receptor tyrosine kinase-3 (FLT3) [ 40 ]. Treatment with anti-EGFR monoclonal antibodies cetuximab or panitumumab is successful in a subset of patients with colorectal cancer, although these stimulate MAPK reactivation, driving secondary resistance [ 76 ].…”