TANKYRASE Inhibition Enhances the Antiproliferative Effect of PI3K and EGFR Inhibition, Mutually Affecting β-CATENIN and AKT Signaling in Colorectal Cancer

Abstract

Overactivation of the WNT/β-CATENIN signaling axis is a common denominator in colorectal cancer. Currently, there is no available WNT inhibitor in clinical practice. Although TANKYRASE (TNKS) inhibitors have been proposed as promising candidates, there are many colorectal cancer models that do not respond positively to TNKS inhibition and Therefore, a combinatorial therapeutic approach combining a TNKS inhibitor (G007-LK) with PI3K (BKM120) and EGFR (erlotinib) inhibitors in colorectal cancer was investigated. The data demonstrate that TNKS inhibition enhances the effect of PI3K and EGFR inhibition in the TNKS inhibitor-sensitive COLO320DM, and in the nonsensitive HCT-15 cell line. In both cell lines, combined TNKS/PI3K/EGFR inhibition is more effective at reducing growth than a dual TNKS/MEK inhibition. TNKS/PI3K/EGFR inhibition affected in a context-dependent manner components of the WNT/β-CATENIN, AKT/mTOR, EGFR, and RAS signaling pathways. TNKS/PI3K/EGFR inhibition also efficiently reduced growth of both COLO320DM and HCT-15 tumor xenografts At the highest doses, tumor xenograft growth was halted without affecting the body weight of the tested animals. Combining TNKS inhibitors with PI3K and EGFR inhibition may expand the therapeutic arsenal against colorectal cancers. .

Wnt Signaling and Drug Resistance in Cancer

“…PI3K inhibition promotes the expression of Wnt ligands in breast cancers, whereas BRAF inhibition upregulates b-catenin signaling through activating the focal adhesion kinase in colorectal cancer. Blocking Wnt/b-catenin signaling by tankyrase inhibitor or PORCN inhibitor can significantly enhance the tumor suppression effect of these small molecular inhibitors targeting the growth factor signaling pathways (Tzeng et al, 2015;Solzak et al, 2017;Chen et al, 2018;Solberg et al, 2018). In EGFRmutated lung cancer, even though EGFR inhibitors are not observed to significantly upregulate Wnt signaling in preclinical studies, Wnt/b-catenin signaling has been shown to drive resistance to EGFR inhibitors in lung cancer cells because tankyrase inhibitor and EGFR inhibitor in combination can synergistically suppress lung cancer cell growth in vitro and in vivo (Casás-Selves et al, 2012;Scarborough et al, 2017).…”

Tankyrase inhibition sensitizes melanoma to PD-1 immune checkpoint blockade in syngeneic mouse models

“…Currently, there are no therapeutic strategies available for targeting WNT/β-catenin signaling to counteract checkpoint inhibitor resistance in melanoma. Here we report that a specific small-molecule tankyrase inhibitor, G007-LK [7][8][9] , attenuates WNT/β-catenin and YAP signaling pathways in the syngeneic murine B16-F10 melanoma model enabling sensitivity to anti-PD-1 immune checkpoint therapy. RNA sequencing of 18 tankyrase inhibitor-treated human melanoma cell lines and B16-F10 cells revealed a transcriptional response profile for a subpopulation.…”

“…Checkpoint inhibitor treatment, including blockade of the PD-1 receptor, has shown limited efficacy against B16-F10 tumors despite strong expression of the ligand PD-L1 on the tumor cells 10 , a feature attributed to low infiltration by effector CD8 + T cells 11,12 . G007-LK [7][8][9] is a potent and specific tankyrase inhibitor that obstructs WNT/β-catenin and YAP signaling through stabilization of the AXIN-based degradosome and AMOT proteins, respectively 8,[13][14][15][16][17] .…”

Tankyrase inhibition sensitizes melanoma to PD-1 immune checkpoint blockade in syngeneic mouse models

“…Checkpoint inhibitor treatment, including blockade of the PD-1 receptor, has shown limited efficacy in the murine B16-F10 melanoma model, despite strong expression of the ligand PD-L1 on the tumor cells 32 ; a feature attributed to low tumor infiltration by effector CD8 + T cells 33,34 . G007-LK is a potent preclinical stage tankyrase inhibitor with a high selectivity towards tankyrase 1 and 2 and a favorable pharmacokinetic profile in mice with an oral bioavailability of 76% and a t 1/2 of 2.6 hours in female mice 23,35,36 .…”