Antibody-Exatecan Conjugates with a Novel Self-immolative Moiety Overcome Resistance in Colon and Lung Cancer.

Unlabelled: Antibody-drug conjugates (ADC) using DNA topoisomerase I inhibitor DXd/SN-38 have transformed cancer treatment, yet more effective ADCs are needed for overcoming resistance. We have designed an ADC class using a novel self-immolative T moiety for traceless conjugation and release of exatecan, a more potent topoisomerase I inhibitor with less sensitivity to multidrug resistance (MDR). Characterized by enhanced therapeutic indices, higher stability, and improved intratumoral pharmacodynamic response, antibody-T moiety-exatecan conjugates targeting HER2, HER3, and TROP2 overcome the intrinsic or treatment resistance of equivalent DXd/SN-38 ADCs in low-target-expression, large, and MDR+ tumors.

Heterogeneity of receptor function in colon carcinoma cells determined by cross-talk between type I insulin-like growth factor receptor and epidermal growth factor receptor.

This study identifies a novel cross-talk paradigm between the type I insulin-like growth factor receptor (IGF1R) and epidermal growth factor receptor (EGFR) in colon cancer cells. IGF1R activation by ligand exposure in growth factor-deprived cells induces Akt activation in the FET, CBS, and GEO colon cancer cell lines. Investigation of IGF1R-mediated signaling pathways using small interfering RNA approaches indicated that, as expected, phosphatidylinositol 3'-kinase (PI3K) was activated by IGF1R.

Blockade of EGFR and ErbB2 by the novel dual EGFR and ErbB2 tyrosine kinase inhibitor GW572016 sensitizes human colon carcinoma GEO cells to apoptosis.

Coexpression of the epidermal growth factor receptor (EGFR) family receptors is found in a subset of colon cancers, which may cooperatively promote cancer cell growth and survival, as heterodimerization is known to provide for diversification of signal transduction. Recently, efforts have been made to develop novel 4-anilinoquinazoline and pyridopyrimidine derivatives to inhibit EGFR and ErbB2 kinases simultaneously. In this study, we tested the efficacy of a novel reversible dual inhibitor GW572016 compared with the selective EGFR and ErbB2 tyrosine kinase inhibitors (TKI) AG1478 and AG879 and their combination, using the human colon adenocarcinoma GEO mode.

Reorganization of ErbB family and cell survival signaling after Knock-down of ErbB2 in colon cancer cells.

The role of the ErbB family in supporting the malignant phenotype was characterized by stable transfection of a single chain antibody (ScFv5R) against ErbB2 containing a KDEL endoplasmic reticulum retention sequence into GEO human colon carcinoma cells. The antibody traps ErbB2 in the endoplasmic reticulum, thereby down-regulating cell surface ErbB2. The transfected cells showed inactivation of ErbB2 tyrosine phosphorylation and reduced heterodimerization of ErbB2 and ErbB3.

Biologic contribution of P1 promoter-mediated expression of ST6Gal I sialyltransferase.

The synthesis of the common and well-documented Siaalpha 2,6 to Galbeta 1,4GlcNAc structure (Sia6LacNAc) is principally mediated by the sialyltransferase ST6Gal I, which is particularly highly expressed in liver, lactating mammary gland, intestinal epithelia of newborn animals, and B cells. Multiple independent promoters govern the expression of Siat1, the ST6Gal I gene. In liver, elevation of hepatic and serum ST6Gal is part of the acute phase reaction, the hepatic response to systemic trauma, and is governed by the inducible, liver-specific promoter-regulatory region, P1.