Recent studies published in the March issue of Molecular Oncology demonstrate new therapeutic strategies for overcoming drug resistance in MAPK pathway targeted cancer treatments.
Eukaryotic cell division is a highly complex and regulated process, whereby mitogen-activate protein kinase (MAPK) signalling pathways play an important role and are ubiquitously conserved . A simplified representation of the RAS/RAF/MEK/ERK pathway is illustrated in Figure 1. Briefly, ligands binding to transmembrane receptor tyrosine kinases (RTK) activate the small G protein (RAS) and the downstream RAF (MAPKKK)-MEK-ERK signalling cascade, which leads to the translocation of ERK to the nucleus resulting in activation of various transcription factors. Somatic mutations in proteins within this cascade (including both phosphorylating kinases and phosphatases) are heavily associated with oncogenesis due to their downstream impact on gene expression and cell cycle progression. For example, point mutations in the RAS (HRAS, KRAS, NRAS) genes are estimated to be involved in up to 30% of all human cancers . The March issue of Molecular Oncology places the spotlight on the recent developments in treating resistant-prone MAPK pathway mutants in patients with cancer.
Mathias Drosten and Mariano Barbacid showcase an optimistic perspective of work targeting KRAS mutant lung adenocarcinomas (LUAD) in the era of personalised medicine . One of the major challenges preventing success of KRAS inhibitors is drug resistance manifesting in patients due to accumulation of further mutations, as well as non-genetic resistant properties conferred by plasticity of the heterogenous tumour. Targeting KRAS for protein degradation has been identified as a potential strategy to circumvent inhibitor resistance. This can be achieved by fusion of KRAS to proteolysis targeting chimeras (PROTACs) or E3 ubiquitin ligases to tigger degradation via the proteasome. Other strategies to overcome inhibitor resistance include the targeting of oncogenic signalling activators and effectors, or components with additional activities within MAPK-independent pathways, such as RAF1. The challenges related to high toxicity of MEK and ERK inhibitors are still a matter of debate, however, combinations of therapeutics at lower concentrations may reopen avenues for several new compounds targeting these kinases currently under clinical evaluation.
A combined approach to MAPK signalling intervention was used in a research article by Carragher et al.. The authors investigated the combination of a novel SRC inhibitors (AZD0424) with MEK inhibitors for cancer treatment . SRC is part of a larger family of nonreceptor tyrosine kinases, that although rarely mutated, may become an oncogenic driver, particularly in response to treatment of KRAS-mutant colorectal cell lines with MEK inhibitors (e.g., trametinib). They also demonstrated in vivo that AZD0424 and MEK inhibitors in combination were more effective at inhibiting tumour growth than trametinib alone. Furthermore, treatment with both drugs generally reduced compensatory signalling (EGFR, FAK, SRC) in vitro and decreased cell viability as well as invasion of trametinib-resistant tumour cells.
Combinatorial approaches may also be used to overcome relapse due to drug resistance in patients suffering from chronic lymphocytic leukaemia (CLL). Skanland et al. demonstrated synergistic potential of a MEK inhibitor and the antiapoptotic protein BCL-2 antagonist venetoclax on CLL cells (5). Interestingly, pre-clinical data suggested that a good predictor for sensitivity to this drug combination were the high expression levels of the antiapoptotic proteins Mcl-1 and Bcl-xL, and an additive effect on CLL cell lines was shown using a Bcl-xL inhibitor in combination with trametinib and venetoclax. The protein profiling work in this study highlighted several treatment vulnerabilities which could be further explored in a clinical setting.
Taken together, large steps have been undertaken to understand and circumvent the mechanism of resistance towards MAPK-pathway inhibitors. Specific combinations of drug therapies seem to be the key to developing more clinically effective treatments of a broad range of cancers.
- Ana Cuenda. (2019). Mitogen-Activated Protein Kinases (MAPK) in Cancer, Editor(s): Paolo Boffetta, Pierre Hainaut, Encyclopedia of Cancer (Third Edition), Academic Press, Pages 472-480, https://doi.org/10.1016/B978-0-12-801238-3.64980-2.
- Santarpia, L., Lippman, S. M., & El-Naggar, A. K. (2012). Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy. Expert opinion on therapeutic targets, 16(1), 103–119. https://doi.org/10.1517/14728222.2011.645805
- Drosten, M. and Barbacid, M. (2022), Targeting KRAS mutant lung cancer: light at the end of the tunnel. Mol Oncol, 16: 1057-1071. https://doi.org/10.1002/1878-0261.13168
- Dawson, J.C., Munro, A., Macleod, K., Muir, M., Timpson, P., Williams, R.J., Frame, M., Brunton, V.G. and Carragher, N.O. (2022), Pathway profiling of a novel SRC inhibitor, AZD0424, in combination with MEK inhibitors for cancer treatment. Mol Oncol, 16: 1072-1090. https://doi.org/10.1002/1878-0261.13151
- Melvold, K., Giliberto, M., Karlsen, L., Ayuda-Durán, P., Hanes, R., Holien, T., Enserink, J., Brown, J.R., Tjønnfjord, G.E., Taskén, K. and Skånland, S.S. (2022), Mcl-1 and Bcl-xL levels predict responsiveness to dual MEK/Bcl-2 inhibition in B-cell malignancies. Mol Oncol, 16: 1153-1170.