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Translational Therapeutics

PAK and PI3K pathway activation confers resistance to KRASG12C inhibitor sotorasib

British Journal of Cancer volume 128, pages 148–159 (2023)Cite this article

Subjects

Abstract

Background

KRAS is a frequently mutated oncogene in human cancer. Clinical studies on the covalent inhibitors of the KRASG12C mutant have reported promising results. However, primary and acquired resistance may limit their clinical use.

Methods

Sotorasib-resistant cell lines were established. We explored the signalling pathways activated in these resistant cell lines and their roles in sotorasib resistance.

Results

The resistant cells exhibited increased cell–matrix adhesion with increased levels of stress fibres and focal adherens. p21-activated kinases (PAKs) were activated in resistant cells, which phosphorylate MEK at serine 298 of MEK and serine 338 of c-Raf to activate the mitogen-activated protein kinase pathway. The PAK inhibitors FRAX597 and FRAX486 in synergy with sotorasib reduced the viability of KRASG12C mutant cancer cells. Furthermore, the PI3K/AKT pathway was constitutively active in sotorasib-resistant cells. The overexpression of constitutively activated PI3K or the knockdown of PTEN resulted in resistance to sotorasib. PI3K inhibitor alpelisib was synergistic with sotorasib in compromising the viability of KRASG12C mutant cancer cells. Moreover, PI3K and PAK pathways formed a mutual positive regulatory loop that mediated sotorasib resistance.

Conclusions

Our results indicate that the cell–matrix interaction-dependent activation of PAK mediates resistance to sotorasib through the activation of MAPK and PI3K pathways.

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Fig. 1: Establishment of sotorasib-resistant cancer cell lines.
Fig. 2: Sotorasib-resistant cancer cells exhibit enhanced cell–matrix adhesion.
Fig. 3: Activation of the Src/PAK/MEK axis in sotorasib-resistant cells.
Fig. 4: PAK inhibitors and sotorasib synergistically kill cancer cells.
Fig. 5: Activation of the PI3K pathway confers resistance to sotorasib.
Fig. 6: Mutual positive regulatory loop between the PI3K and PAK pathways regulates cellular sensitivity to sotorasib and the antitumour effects of the combination of sotorasib with FRAX597 or alpelisib in vivo.

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Data availability

The mRNA sequencing data were deposited to the National Center for Biotechnology Information Genome Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/) under the accession number GSE178479. Other data sets generated and/or analysed during this study are available from the corresponding author on reasonable request.

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Acknowledgements

We gratefully acknowledge technical support from the Second and Eighth Core Labs of National Taiwan University Hospital, the Translational Core Facility of Taipei Medical University, and RNA Technology Platform and Gene Manipulation Core, Academia Sinica.

Funding

This work was supported by the Ministry of Science and Technology, Taiwan [grant numbers 109-2314-B-002-084 and 110-2314-B-002-173].

Author information

Author notes

  1. These authors contributed equally: Chien-Hui Chan, Li-Wen Chiou.

Authors and Affiliations

  1. Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan

    Chien-Hui Chan, Li-Wen Chiou, Tsai-Yu Lee & Yung-Ming Jeng

  2. Joint Biobank, Office of Human Research, Taipei Medical University, Taipei, Taiwan

    Yun-Ru Liu & Tsung-Han Hsieh

  3. Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan

    Ching-Yao Yang

  4. Department of Surgery, College of Medicine, National Taiwan University, Taipei, Taiwan

    Ching-Yao Yang

  5. Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan

    Yung-Ming Jeng

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  1. Chien-Hui Chan
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Contributions

C-YY and Y-MJ conceptualised the study and designed the experiments and provided financial support. C-HC, L-WC, and T-YL performed the experiments. Y-RL and T-HH collected the bioinformatics data. C-YY, L-WC, and Y-MJ interpreted the data and drafted the manuscript. All authors discussed the results; reviewed and revised the manuscript; and approved the final version of the manuscript.

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Correspondence to Ching-Yao Yang or Yung-Ming Jeng.

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Chan, CH., Chiou, LW., Lee, TY. et al. PAK and PI3K pathway activation confers resistance to KRASG12C inhibitor sotorasib. Br J Cancer 128, 148–159 (2023). https://doi.org/10.1038/s41416-022-02032-w

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