S6K1 blockade overcomes acquired resistance to EGFR-TKIs in non-small cell lung cancer

Abstract

The development of resistance to EGFR Tyrosine kinase inhibitors (TKIs) in NSCLC with activating EGFR mutations is a critical limitation of this therapy. In addition to genetic alterations such as EGFR secondary mutation causing EGFR-TKI resistance, compensatory activation of signaling pathways without interruption of genome integrity remains to be defined. In this study, we identified S6K1/MDM2 signaling axis as a novel bypass mechanism for the development of EGFR-TKI resistance. The observation of S6K1 as a candidate mechanism for resistance to EGFR TKI therapy was investigated by interrogation of public databases and a clinical cohort to establish S6K1 expression as a prognostic/predictive biomarker. The role of S6K1 in TKI resistance was determined in in vitro gain-and-loss of function studies and confirmed in subcutaneous and orthotopic mouse lung cancer models. Blockade of S6K1 by a specific inhibitor PF-4708671 synergistically enhanced the efficacy of TKI without showing toxicity. The mechanistic study showed the inhibition of EGFR caused nuclear translocation of S6K1 for binding with MDM2 in resistant cells. MDM2 is a downstream effector of S6K1-mediated TKI resistance. Taken together, we present evidence for the reversal of resistance to EGFR TKI by the addition of small molecule S6K1/MDM2 antagonists that could have clinical benefit.

ALKBH5-HOXA10 loop-mediated JAK2 m6A demethylation and cisplatin resistance in epithelial ovarian cancer

“…About 5× 10 6 cells were injected subcutaneously into the axilla of the female athymic BALB/C nude mice (4 week-old, 18-20 g). When the average tumor size reached approximately 100mm 3 (after 1 week), mice were then randomized into two groups and treated with cisplatin (5 mg/kg) or normal saline (NS) weekly. Tumor width (W) and length (L) was measured every week, and the volume (V) of the tumor was calculated as the formula V = (W 2 × L)/2.…”

“…Several mechanisms, including activation of oncogenes, mutation of antioncogene, and dysregulation of cancer-associated signaling pathway, are involved in chemoresistance [3][4][5]. N6-methyladenosine (m6A) modification is one of the most prevalent mRNA modification and influences mRNA transcription, stabilization, and translation [6].…”

Drug mechanism enrichment analysis improves prioritization of therapeutics for repurposing

“…4F). Indeed, this bioinformatic result is supported by the observation that MDM2 mediates resistance to EGFR inhibitors in mouse models of NSCLC (Shen et al ., 2020). Furthermore, our analysis of BRAF inhibitor sensitivity suggested that tumors sensitive to BRAF inhibitors would also be sensitive to MEK inhibitors (Fig.…”

MiRNA-30e downregulation increases cancer cell proliferation, invasion and tumor growth through targeting RPS6KB1

“…Recent studies have reported that the gain of function is the central role of RPS6KB1 in resistance to tyrosine kinase (TKI) in lung cancer, and its specific inhibitor PF-4708671 shows synergistic effect to enhance TKIs efficacy to suppress tumor growth in vivo [ 33 ]. Several studies have shown that single reagent treatment often fails in clinical practice, additional studies are necessary to optimize combination therapies that include RPS6KB1 inhibitor to treat EC.…”