The identification of novel therapeutic strategies for metastatic colorectal cancer (mCRC) patients harbouring KRAS mutations represents an unmet clinical need. In this study, we aimed to clarify the role of p21-activated kinases (Paks) as therapeutic target for KRAS-mutated CRC.
Paks expression and activation levels were evaluated in a cohort of KRAS-WT or -mutated CRC patients by immunohistochemistry. The effects of Paks inhibition on tumour cell proliferation and signal transduction were assayed by RNAi and by the use of three pan-Paks inhibitors (PF-3758309, FRAX1036, GNE-2861), evaluating CRC cells, spheroids and tumour xenografts’ growth.
Paks activation positively correlated with KRAS mutational status in both patients and cell lines. Moreover, genetic modulation or pharmacological inhibition of Paks led to a robust impairment of KRAS-mut CRC cell proliferation. However, Paks prolonged blockade induced a rapid tumour adaptation through the hyper-activation of the mTOR/p70S6K pathway. The addition of everolimus (mTOR inhibitor) prevented the growth of KRAS-mut CRC tumours in vitro and in vivo, reverting the adaptive tumour resistance to Paks targeting.
In conclusion, our results suggest the simultaneous blockade of mTOR and Pak pathways as a promising alternative therapeutic strategy for patients affected by KRAS-mut colorectal cancer.
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This work was supported by AIRC IG 21339 grant (RB); MFAG 21505 – 2018 grant (LF) and Lilly (LF); MFAG 27826 – 2022 grant (AS). DE was supported by AIRC fellowship for Italy – 26795.
AS reports honoraria from Eli Lilly, MSD, and Janssen and travel support from Bristol-Myers Squibb and AstraZeneca. LF declares the following competing interests: consultant and advisory board for Seagen, Amgen, BMS, MSD, Jansen and Pierre Fabre Pharma. RB declares the following competing interests: consultant and advisory board for BMS, MSD, Pfizer, AstraZeneca, Lilly and Novartis. The remaining authors declare no competing interests.
Ethics approval and consent to participate
CRC samples were retrospectively analysed at the Pathology Unit, University of Campania “L. Vanvitelli”. All patients agreed to participate in the study based on informed consent. Research Ethics Committee of the University of Campania “L. Vanvitelli” – AORN “Ospedale dei Colli” approved the study (reference n.0019530/2016). The study was performed in accordance with the Declaration of Helsinki.
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Belli, S., Pesapane, A., Servetto, A. et al. Combined blockade of mTOR and p21-activated kinases pathways prevents tumour growth in KRAS-mutated colorectal cancer. Br J Cancer 129, 1071–1082 (2023). https://doi.org/10.1038/s41416-023-02390-z