EGFR and c-MET Cooperate to Enhance Resistance to PARP Inhibitors in Hepatocellular Carcinoma

Abstract

PARP1 inhibitors (PARPi) are currently used in the clinic for the treatment of ovarian and breast cancers, yet their therapeutic efficacy against hepatocellular carcinoma (HCC) has been disappointing. To ensure therapeutic efficacy of PARPi against HCC, a disease often diagnosed at intermediate to advanced stages with no effective treatment options, it is critical to identify not only biomarkers to predict PARPi resistance but also rational treatments to overcome this. Here, we report that a heterodimer of EGFR and MET interacts with and phosphorylates Y907 of PARP1 in the nucleus, which contributes to PARPi resistance. Inhibition of both EGFR and MET sensitized HCC cells to PARPi, and both EGFR and MET are known to be overexpressed in HCC. This report provides an explanation for the poor efficacy of PARPi against HCC and suggests combinatorial treatment consisting of EGFR, MET, and PARP inhibitors may be an effective therapeutic strategy in HCC.

Circulating exosome‐derived bona fide long non‐coding RNAs predicting the occurrence and metastasis of hepatocellular carcinoma

“…9,17,18 The annotated biomarkers extracted from tumour tissues or cell-free plasma has been proved might indicate the occurrence or recurrence of HCC. 19,20 HCC is one of the most common human malignant tumours worldwide and was proved with high mortality rates. 21 Circulating ncRNAs have been well documented based on the crucial role during the pathogenesis and development of human cancer.…”

Blocking c-MET/ERBB1 Axis Prevents Brain Metastasis in ERBB2+ Breast Cancer

“…The synergistic regulation of signaling mediated by ERBB1 and c-MET receptors is important in the regulation of cancer progression, metastasis, and drug resistance [ 16 , 28 , 30 ]. The downstream protein kinase B (PKB/Akt) and extracellular signal-regulated kinase (ERK) are co-regulated by both ERBB1 and c-MET receptors [ 31 ].…”

Synergistic Anti-Tumour Effect of Syk Inhibitor and Olaparib in Squamous Cell Carcinoma: Roles of Syk in EGFR Signalling and PARP1 Activation

“…In glioblastoma cells, EGFRvIII overexpression causes increased ROS-dependent DNA strand break accumulation and PARP activation, and reduced DNA repair gene expression, including PARP1, results in improved patient survival [45]. In hepatocellular carcinoma, EGFR and c-MET cooperate to enhance resistance to PARP inhibitors [46]. Furthermore, a heterodimer of EGFR and MET can phosphorylate Y907 of PARP1 in the nucleus of hepatocellular carcinoma and contribute to this resistance [46].…”

“…In hepatocellular carcinoma, EGFR and c-MET cooperate to enhance resistance to PARP inhibitors [46]. Furthermore, a heterodimer of EGFR and MET can phosphorylate Y907 of PARP1 in the nucleus of hepatocellular carcinoma and contribute to this resistance [46]. In pancreatic cancer cells, adaptive expression of EGF following exposure to ionising radiation may induce radio-sensitisation of cells through the induction of the cyclin D1/p53/PARP pathway [47].…”