Targeting ErbB and tankyrase1/2 prevent the emergence of drug-tolerant persister cells in ALK-positive lung cancer.

Targeting the drug tolerant persister (DTP) state in cancer cells should prevent further development of resistance mechanisms. This study explored combination therapies to inhibit alectinib-induced DTP cell formation from anaplastic lymphoma kinase-positive non-small cell lung cancer (ALK + NSCLC) patient-derived cells. After drug-screening 3114 compounds, pan-HER inhibitors (ErbB pathway) and tankyrase1/2 inhibitors (Wnt/β-catenin signaling) emerged as top candidates to inhibit alectinib-induced DTP cells growth.

Combined blockade of GPX4 and activated EGFR/HER3 bypass pathways inhibits the development of ALK-inhibitor-induced tolerant persister cells in ALK-fusion-positive lung cancer.

Cancers can develop resistance to treatment with ALK tyrosine kinase inhibitors (ALK-TKIs) via emergence of a subpopulation of drug-tolerant persister (DTP) cells that can survive initial drug treatment long enough to acquire genetic aberrations. DTP cells are thus a potential therapeutic target. We generated alectinib-induced DTP cells from a patient-derived ALK non-small-cell lung cancer (NSCLC) cell line and screened 3114 agents in the anticancer compounds library (TargetMol).

FGFR blockade inhibits targeted therapy-tolerant persister in basal FGFR1- and FGF2-high cancers with driver oncogenes.

Cancer cell resistance arises when tyrosine kinase inhibitor (TKI)-targeted therapies induce a drug-tolerant persister (DTP) state with growth via genetic aberrations, making DTP cells potential therapeutic targets. We screened an anti-cancer compound library and identified fibroblast growth factor receptor 1 (FGFR1) promoting alectinib-induced anaplastic lymphoma kinase (ALK) fusion-positive DTP cell's survival. FGFR1 signaling promoted DTP cell survival generated from basal FGFR1- and fibroblast growth factor 2 (FGF2)-high protein expressing cells, following alectinib treatment, which is blocked by FGFR inhibition.

The molecular rationale for the combination of polatuzumab vedotin plus rituximab in diffuse large B-cell lymphoma.

Polatuzumab vedotin (Pola) is an antibody-drug conjugate that targets the B-cell antigen CD79b and delivers monomethyl auristatin E (MMAE). It is approved in combination with bendamustine and rituximab (Rit) for relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). Understanding the molecular basis of Pola combination therapy with Rit, the key component for the treatment of DLBCL, is important to establish the effective treatment strategies against r/r DLBCL.

Coadministration with bendamustine restores the antitumor activity of obinutuzumab in obinutuzumab-resistant tumors.

Background: The glycoengineered, humanized anti-CD20 antibody obinutuzumab is indicated for previously untreated or relapsed/refractory CD20-positive follicular lymphoma (FL). However, the effectiveness of obinutuzumab retreatment in relapsed/refractory FL after prior obinutuzumab-containing therapy is unclear. To address this issue, we investigated the antitumor activity of obinutuzumab plus bendamustine in obinutuzumab-resistant tumors established from a human non-Hodgkin lymphoma xenograft model.

Resistance to obinutuzumab-induced antibody-dependent cellular cytotoxicity caused by abnormal Fas signaling is overcome by combination therapies.

Background: Obinutuzumab, a Type II anti-CD20 antibody, is used to treat follicular lymphoma. A major mode of action of obinutuzumab is antibody-dependent cellular cytotoxicity (ADCC). Knowledge of the mechanisms of resistance to obinutuzumab is important for the development of next-line strategies to follow obinutuzumab-containing therapy, including obinutuzumab retreatment.

Obinutuzumab in Combination with Chemotherapy Enhances Direct Cell Death in CD20-Positive Obinutuzumab-resistant Non-Hodgkin Lymphoma Cells.

Follicular lymphoma commonly recurs and is difficult to cure. Obinutuzumab is a humanized glycoengineered type II anti-CD20 antibody with a mode of action that includes induction of antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and direct cell death. There is no evidence on the effectiveness of retreatment with obinutuzumab in patients with prior obinutuzumab treatment.

Combination efficacy of pertuzumab and trastuzumab for trastuzumab emtansine-resistant cells exhibiting attenuated lysosomal trafficking or efflux pumps upregulation.

Purpose: Trastuzumab emtansine (T-DM1) is the standard treatment in the current second-line therapy of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. However, a useful therapy after T-DM1 resistance has not been established. In this study, we established two different HER2-positive T-DM1-resistant cancer cells and evaluated the antitumor effect of trastuzumab in combination with pertuzumab (TRAS + PER).

Reconstruction of Par-dependent polarity in apolar cells reveals a dynamic process of cortical polarization.

Cellular polarization is fundamental for various biological processes. The Par network system is conserved for cellular polarization. Its core complex consists of Par3, Par6, and aPKC.

Tre1 GPCR signaling orients stem cell divisions in the Drosophila central nervous system.

During development, directional cell division is a major mechanism for establishing the orientation of tissue growth. Drosophila neuroblasts undergo asymmetric divisions perpendicular to the overlying epithelium to produce descendant neurons on the opposite side, thereby orienting initial neural tissue growth. However, the mechanism remains elusive.

Ultradian oscillators in somite segmentation and other biological events.

Somite formation occurs every 2 hours in mouse embryos by periodic segmentation of the anterior ends of the presomitic mesoderm, and this process is controlled by a biological clock called the segmentation clock. During this process, the basic helix-loop-helix gene Hes7 is cyclically expressed, and each cycle leads to generation of a bilateral pair of somites. Both sustained expression and loss of expression of Hes7 result in severe somite fusion, indicating that Hes7 constitutes an essential component of the segmentation clock.

Ultradian oscillations of Stat, Smad, and Hes1 expression in response to serum.

Serum response has been used as a model for studying signaling transduction for many biological events such as cell proliferation and survival. Although expression of many genes is up- or down-regulated after serum stimulation, the Notch effector Hes1 displays oscillatory response. However, the precise mechanism and biological significance of this oscillation remain to be determined.

Iris-derived cells from adult rodents and primates adopt photoreceptor-specific phenotypes.

Purpose: The purpose of this study was to investigate the effects of various genes related to photoreceptor development on rodent and primate iris cells and the potential of iris cells as donor cells for retinal transplantation.

Methods: Adult rat and monkey iris tissue were cultured in serum-free medium containing basic fibroblast growth factor. Gene deliveries of Crx, Nrl, NeuroD and some combinations (Crx-Nrl, Crx-NeuroD) were performed with recombinant retrovirus.

Oscillatory expression of the bHLH factor Hes1 regulated by a negative feedback loop.

Transcription of messenger RNAs (mRNAs) for Notch signaling molecules oscillates with 2-hour cycles, and this oscillation is important for coordinated somite segmentation. However, the molecular mechanism of such oscillation remains to be determined. Here, we show that serum treatment of cultured cells induces cyclic expression of both mRNA and protein of the Notch effector Hes1, a basic helix-loop-helix (bHLH) factor, with 2-hour periodicity.