An EGFR/HER2-targeted conjugate sensitizes gemcitabine-sensitive and resistant pancreatic cancer through different SMAD4-mediated mechanisms

Abstract

Chemoresistance limits its clinical implementation for pancreatic ductal adenocarcinoma (PDAC). We previously generated an EGFR/HER2 targeted conjugate, dual-targeting ligand-based lidamycin (DTLL), which shows a highly potent antitumor effect. To overcome chemoresistance in PDAC, we aim to study DTLL efficacy when combined with gemcitabine and explore its mechanisms of action. DTLL in combination with gemcitabine show a superior inhibitory effect on the growth of gemcitabine-resistant/sensitive tumors. DTLL sensitizes gemcitabine efficacy via distinct action mechanisms mediated by mothers against decapentaplegic homolog 4 (SMAD4). It not only prevents neoplastic proliferation via ATK/mTOR blockade and NF-κB impaired function in SMAD4-sufficient PDACs, but also restores SMAD4 bioactivity to trigger downstream NF-κB-regulated signaling in SMAD4-deficient tumors and to overcome chemoresistance. DTLL seems to act as a SMAD4 module that normalizes its function in PDAC, having a synergistic effect in combination with gemcitabine. Our findings provide insight into a rational SMAD4-directed precision therapy in PDAC.

Advanced renal pelvis carcinoma patient with an ERBB2 insertion mutation: a case report

“…Additionally, research has shown that loss of SMAD4 function can contribute to reduced sensitivity to EGFR/ERBB2-targeted drugs. [31][32][33] Unfortunately, because of the limited availability of effective therapeutics against KRAS and SMAD4 mutations, we were unable to control the disease progression.…”

SMAD Proteins in TGF-β Signalling Pathway in Cancer: Regulatory Mechanisms and Clinical Applications

“…Yao et al developed an EGFR/HER2-targeting conjugate, the dual-target ligand-based lidamycin (DTLL), which prevents tumour proliferation in SMAD4/DPC4-deficient PDAC through ATK/mTOR blockade and impaired NF-κB function, and also restores SMAD4/DPC4 bioactivity, triggering downstream NF-κB regulation in SMAD4/DPC4-deficient tumours of signalling to overcome chemoresistance. In combination with gemcitabine, DTLL exhibits a unique mechanism of action similar to that of SMAD4/DPC4, showing superior inhibition of the growth of gemcitabine-resistant/sensitive tumours [86]. Fei et al found that the addition of hydroxychloroquine to neoadjuvant chemotherapy in patients with PDA may improve the therapeutic response in SMAD4/DPC4-deficient patients.…”

Exploring the therapeutic mechanisms of Gleditsiae Spina acting on pancreatic cancervianetwork pharmacology, molecular docking and molecular dynamics simulation

“…The ve-year survival rate for pancreatic cancer is below 5%. 1,2 The majority of patients are diagnosed with advanced-stage disease that cannot be treated surgically, resulting in a life expectancy of typically less than six months. 3,4 Pancreatic cancer is a multifactorial disease that arises from a combination of factors.…”