New strategy for suppressing the growth of lung cancer cells harboring mutations in the ATP‐binding region of EGFR by targeting the molecular motor MYO1D

Abstract

In this study, we describe that the molecular motor MYO1D holds both wild-type and mutant EGFRs in the plasma membrane via interaction of MYO1D with a C-terminal portion of the kinase domain (C-terminal substrate-binding lobe or C-lobe) that does not contain the ATP-binding region. Further, we show that the knockdown of MYO1D suppresses the growth, invasion and downstream signals of lung cancer and glioblastoma cells expressing mutant EGFR or mutant ErbB2, which have resistance to afatinib, osimertinib, and cetuximab. This represents a new strategy of reducing the wild-type and mutant EGFRs themselves to treat acquired resistance in various EGFR-overexpressing cancers harboring mutations in the ATP-binding region, which is directly targeted by most tyrosine kinase inhibitors (TKIs).The main challenge during EGFR-targeted therapy in nonsmall cell lung cancer (NSCLC) is the acquisition of resistance to EGFR-TKIs. 1 Mechanisms of therapeutic resistance include mutations of the kinase domain at the T790M or C797S codon that interfere with TKI access to the active site, which is difficult to treat with standard therapeutic options. 2,3 The EGFR (ErbB1) and ErbB2 pathways are functionally linked and pivotal in the progression of NSCLC. 1 Overexpression of ErbB2 has been reported in about 20% of lung cancers in which mutant ErbB2 is more potent than the wild type in promoting tumorigenicity. 4,5 Thus, combined inhibition of ErbB receptors could prevent a molecular feedback loop responsible for acquired resistance to existing anti-ErbB agents. 6,7 To this aim, a new strategy can be considered: a single multitargeted agent and a new class of anti-ErbB agent with a different molecular mechanism.

Upregulated SPAG6 promotes acute myeloid leukemia progression through MYO1D that regulates the EGFR family expression

“…34,35 Ko and colleagues reported that the proliferation, motility, and survival of nonsmall-cell lung cancer cells were obviously reduced when MYO1D was knocked down, resulting in reduced cytomembrane levels of EGFR or mutant ERBB2 after MYO1D deficiency. 36 A previous study reported that MYO1D binds to the nonphosphorylated domain of the EGFR family and anchors it to the cytomembrane to avoid degradation, while overexpressed MYO1D activates the downstream RTK signaling pathway by upregulating EGFR on the tumor cytomembrane. 23 EGFR signaling is activated in multiple tumors, such as lung cancer, colorectal cancer, and leukemia, and it plays a key role in tumorigenesis and progression by promoting various cellular processes.…”

A peptide interfering with the dimerization of oncogenic KITENIN protein and its stability suppresses colorectal tumour progression

“…Cytoplasmic and membrane fractions were prepared by a subcellular protein fractionation kit for cultured cells (Thermo Scientific) as previously described. 24 Each fraction was resolved by SDS–PAGE and probed for KITENIN by tagging antibodies to V5 and Myc. Fraction purity was analysed by probing for tubulin for the cytoplasm and Na + –K + ATPase for the membrane protein.…”

QiDongNing induces lung cancer cell apoptosis via triggering P53/DRP1‐mediated mitochondrial fission

“…7,8 The combination of fused mitochondrial structure is associated with increased ATP generation and reduced ROS levels, whereas fragmented mitochondrial structure results in mitochondrial uncoupling, decreased mitochondrial membrane potential and impaired ATP production, ultimately leading to apoptosis. 9 Deletion of the p53 gene causes mitochondrial oxidative phosphorylation and glycolysis, thus impairing metabolic reprogramming and mitochondrial metabolic function in malignant cells. 10 Activating pro-apoptotic factors and inducing mitochondrial outer membrane permeabilization are important functions of p53.…”

“…These factors lead to impaired energy metabolism, loss of control over cell differentiation and growth and disruptions in the cell cycle 7,8 . The combination of fused mitochondrial structure is associated with increased ATP generation and reduced ROS levels, whereas fragmented mitochondrial structure results in mitochondrial uncoupling, decreased mitochondrial membrane potential and impaired ATP production, ultimately leading to apoptosis 9 …”