The importance of being CAFs (in cancer resistance to targeted therapies)

In the last two decades, clinical oncology has been revolutionized by the advent of targeted drugs. However, the efficacy of these therapies is significantly limited by primary and acquired resistance, that relies not only on cell-autonomous mechanisms but also on tumor microenvironment cues. Cancer-associated fibroblasts (CAFs) are extremely plastic cells of the tumor microenvironment. They not only produce extracellular matrix components that build up the structure of tumor stroma, but they also release growth factors, chemokines, exosomes, and metabolites that affect all tumor properties, including response to drug treatment. The contribution of CAFs to tumor progression has been deeply investigated and reviewed in several works. However, their role in resistance to anticancer therapies, and in particular to molecular therapies, has been largely overlooked. This review specifically dissects the role of CAFs in driving resistance to targeted therapies and discusses novel CAF targeted therapeutic strategies to improve patient survival

HER2 Copy Number and Resistance Mechanisms in Patients with HER2-positive Advanced Gastric Cancer Receiving Initial Trastuzumab-based Therapy in JACOB Trial

Resistance mechanisms; Advanced gastric cancer; TrastuzumabMecanismos de resistencia; Cáncer gástrico avanzado; TrastuzumabMecanismes de resistència; Càncer gàstric avançat; TrastuzumabPurpose: In JACOB trial, pertuzumab added to trastuzumab-chemotherapy did not significantly improve survival of patients with HER2-positive metastatic gastric cancer, despite 3.3 months increase versus placebo. HER2 copy-number variation (CNV) and AMNESIA panel encompassing primary resistance alterations (KRAS/PIK3CA/MET mutations, KRAS/EGFR/MET amplifications) may improve patients’ selection for HER2 inhibition. Experimental Design: In a post hoc analysis of JACOB on 327 samples successfully sequenced by next-generation sequencing (NGS; Oncomine Focus DNA), HER2 CNV, HER2 expression by IHC, and AMNESIA were correlated with overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) by univariable/multivariable models. Results: Median HER2 CNV was 4.7 (interquartile range, 2.2–16.9). HER2 CNV-high versus low using the median as cutoff was associated with longer median PFS (10.5 vs. 6.4 months; HR = 0.48; 95% confidence interval: 0.38–0.62; P < 0.001) and OS (20.3 vs. 13.0 months; HR = 0.54; 0.42–0.72; P < 0.001). Combining HER2 CNV and IHC improved discriminative ability, with better outcomes restricted to HER2-high/HER2 3+ subgroup. AMNESIA positivity was found in 51 (16%), with unadjusted HR = 1.35 (0.98–1.86) for PFS; 1.43 (1.00–2.03) for OS. In multivariable models, only HER2 CNV status remained significant for PFS (P < 0.001) and OS (P = 0.004). Higher ORR was significantly associated with IHC 3+ [61% vs. 34% in 2+; OR = 3.11 (1.89–5.17)] and HER2-high [59% vs. 43% in HER2-low; OR = 1.84 (1.16–2.94)], with highest OR in the top CNV quartile. These biomarkers were not associated with treatment effect of pertuzumab. Conclusions: HER2 CNV-high assessed by NGS may be associated with better ORR, PFS, and OS in a JACOB subgroup, especially if combined with HER2 3+. The negative prognostic role of AMNESIA requires further clinical validation

Semaphorin 4D regulates gonadotropin hormone–releasing hormone-1 neuronal migration through PlexinB1–Met complex

In mammals, reproduction is dependent on specific neurons secreting the neuropeptide gonadotropin hormone–releasing hormone-1 (GnRH-1). These cells originate during embryonic development in the olfactory placode and migrate into the forebrain, where they become integral members of the hypothalamic–pituitary–gonadal axis. This migratory process is regulated by a wide range of guidance cues, which allow GnRH-1 cells to travel over long distances to reach their appropriate destinations. The Semaphorin4D (Sema4D) receptor, PlexinB1, is highly expressed in the developing olfactory placode, but its function in this context is still unknown. Here, we demonstrate that PlexinB1-deficient mice exhibit a migratory defect of GnRH-1 neurons, resulting in reduction of this cell population in the adult brain. Moreover, Sema4D promotes directional migration in GnRH-1 cells by coupling PlexinB1 with activation of the Met tyrosine kinase (hepatocyte growth factor receptor). This work identifies a function for PlexinB1 during brain development and provides evidence that Sema4D controls migration of GnRH-1 neurons

Activation of HER family members in gastric carcinoma cells mediates resistance to MET inhibition

<p>Abstract</p> <p>Background</p> <p>Gastric cancer is the second leading cause of cancer mortality in the world. The receptor tyrosine kinase MET is constitutively activated in many gastric cancers and its expression is strictly required for survival of some gastric cancer cells. Thus, MET is considered a good candidate for targeted therapeutic intervention in this type of tumor, and MET inhibitors recently entered clinical trials. One of the major problems of therapies targeting tyrosine kinases is that many tumors are not responsive to treatment or eventually develop resistance to the drugs. Perspective studies are thus mandatory to identify the molecular mechanisms that could cause resistance to these therapies.</p> <p>Results</p> <p>Our <it>in vitro </it>and <it>in vivo </it>results demonstrate that, in MET-addicted gastric cancer cells, the activation of HER (Human Epidermal Receptor) family members induces resistance to MET silencing or inhibition by PHA-665752 (a selective kinase inhibitor). We provide molecular evidences highlighting the role of EGFR, HER3, and downstream signaling pathways common to MET and HER family in resistance to MET inhibitors. Moreover, we show that an <it>in vitro </it>generated gastric cancer cell line resistant to MET-inhibition displays overexpression of HER family members, whose activation contributes to maintenance of resistance.</p> <p>Conclusions</p> <p>Our findings predict that gastric cancer tumors bearing constitutive activation of HER family members are poorly responsive to MET inhibition, even if this receptor is constitutively active. Moreover, the appearance of these alterations might also be responsible for the onset of resistance in initially responsive tumors.</p

YAP-Dependent AXL Overexpression Mediates Resistance to EGFR Inhibitors in NSCLC

The Yes-associated protein (YAP) is a transcriptional co-activator upregulating genes that promote cell growth and inhibit apoptosis. The main dysregulation of the Hippo pathway in tumors is due to YAP overexpression, promoting epithelial to mesenchymal transition, cell transformation, and increased metastatic ability. Moreover, it has recently been shown that YAP plays a role in sustaining resistance to targeted therapies as well. In our work, we evaluated the role of YAP in acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in lung cancer. In EGFR-addicted lung cancer cell lines (HCC4006 and HCC827) rendered resistant to several EGFR inhibitors, we observed that resistance was associated to YAP activation. Indeed, YAP silencing impaired the maintenance of resistance, while YAP overexpression decreased the responsiveness to EGFR inhibitors in sensitive parental cells. In our models, we identified the AXL tyrosine kinase receptor as the main YAP downstream effector responsible for sustaining YAP-driven resistance: in fact, AXL expression was YAP dependent, and pharmacological or genetic AXL inhibition restored the sensitivity of resistant cells to the anti-EGFR drugs. Notably, YAP overactivation and AXL overexpression were identified in a lung cancer patient upon acquisition of resistance to EGFR TKIs, highlighting the clinical relevance of our in vitro results. The reported data demonstrate that YAP and its downstream target AXL play a crucial role in resistance to EGFR TKIs and suggest that a combined inhibition of EGFR and the YAP/AXL axis could be a good therapeutic option in selected NSCLC patients

Tumor angiogenesis and progression are enhanced by Sema4D produced by tumor-associated macrophages

Increased evidence suggests that cancer-associated inflammation supports tumor growth and progression. We have previously shown that semaphorin 4D (Sema4D), a ligand produced by different cell types, is a proangiogenic molecule that acts by binding to its receptor, plexin B1, expressed on endothelial cells (Conrotto, P., D. Valdembri, S. Corso, G. Serini, L. Tamagnone, P.M. Comoglio, F. Bussolino, and S. Giordano. 2005. Blood. 105:4321–4329). The present work highlights the role of Sema4D produced by the tumor microenvironment on neoplastic angiogenesis. We show that in an environment lacking Sema4D, the ability of cancer cells to generate tumor masses and metastases is severely impaired. This condition can be explained by a defective vascularization inside the tumor. We demonstrate that tumor-associated macrophages (TAMs) are the main cells producing Sema4D within the tumor stroma and that their ability to produce Sema4D is critical for tumor angiogenesis and vessel maturation. This study helps to explain the protumoral role of inflammatory cells of the tumor stroma and leads to the identification of an angiogenic molecule that might be a novel therapeutic target