Therapeutic resistance in cancer is responsible for numerous cancer deaths in clinical practice. While target mutations are well recognized as the basis of genetic resistance to targeted therapy, nontarget mutation resistance (or nongenetic resistance) remains poorly characterized. Despite its complex and unintegrated mechanisms in the literature, nongenetic resistance is considered from our perspective to be a collective response of innate or acquired resistant subpopulations in heterogeneous tumors to therapy. These subpopulations, e.g., cancer stem-like cells, cancer cells with epithelial-to-mesenchymal transition, and drug-tolerant persisters, are protected by their resistance traits at cellular and molecular levels. This review summarizes recent advances in the research on resistant populations and their resistance traits. NOTCH signaling, as a central regulator of nongenetic resistance, is discussed with a special focus on its canonical maintenance of resistant cancer cells and noncanonical regulation of their resistance traits. This novel view of canonical and noncanonical NOTCH signaling pathways is translated into our proposal of reshaping therapeutic strategies targeting NOTCH signaling in resistant cancer cells. We hope that this review will lead researchers to study the canonical and noncanonical arms of NOTCH signaling as an integrated resistant mechanism, thus promoting the development of innovative therapeutic strategies.
Neoplasms/metabolism* ; Receptors, Notch/metabolism* ; Disease Resistance/physiology* ; Signal Transduction/physiology* ; Humans ; Drug Resistance, Neoplasm/physiology* ; Molecular Targeted Therapy/methods*

Objective:To investigate the pathological characteristics in chronic HBV infection patients with different upper limits of alanine aminotransferase (ALT) normal values and the influencing factors of liver tissue injury.Methods:The clinical data of 667 chronic HBV infection patients with ALT<40 U/L and HBV DNA loads >30 IU/mL who received liver biopsy in Zhenhai District Hospital of Traditional Chinese Medicine and Hwa Mei Hospital from January 2014 to December 2020 were retrospectively analyzed. The enrolled patients were divided into ALTⅠ group (<30 U/L for males, <19 U/L for females), ALTⅡ group (≥30 U/L and <35 U/L for males, ≥19 U/L and <25 U/L for females) and ALT Ⅲ group (≥35 U/L and <40 U/L for males, ≥25 U/L and <40 U/L for females). According to the degree of liver inflammation (G) and fibrosis stage (S), the enrolled patients were divided into non-significant damage group (G<2 and S<2) and significant damage group (≥G2 or/and ≥S2). Ridit analysis was used to compare the G/S composition ratio among three ALT groups, Logistic regression was used to analyze the risk factors of liver injury, the receiver operating characteristic curve (ROC) and the area under the curve (AUC) were used to analyze the optimal diagnostic threshold of ALT.Results:There were significant differences in the composition ratio of G and S among the three ALT groups( χ2=13.926 and 14.702, both P<0.001). The constituent ratios of significant liver pathological damage in the three groups of ALT levels were 26.05% (99/380), 32.03% (41/128) and 46.54% (74/159), respectively( χ2=21.596, P<0.001). Multivariate logistic regression analysis showed that high white/globulin ratio and PLT counts( OR=0.246 and 0.986, both P<0.001)were the protective factors for liver tissue injury; while negative HBcAg staining and elevated ALT and GGT levels ( OR=3.797, 1.053 and 1.013, P<0.001 or <0.05) were the risk factors of liver injury. ROC curve demonstrated the ALT threshold of liver tissue damage in male and female patients were 25.6 U/L and 25.5 U/L. Conclusions:In chronic HBV infection patients with normal ALT, with the increase of ALT level, the degree of liver tissue pathological damage may become more severe. The study demonstrates that it is necessary to lower the ALT threshold for protecting patients from liver tissue pathological damage.