Management of Oligoprogression in Patients with Metastatic NSCLC Harboring ALK Rearrangements

Personalized treatment based on driver molecular alterations, such as ALK rearrangement, has revolutionized the therapeutic management of advanced oncogene addicted NSCLC patients. Multiple effective ALK tyrosine kinase inhibitors (TKIs), with the amelioration of the activity at central nervous system level, are now available, leading to substantial prognosis improvement. The exposure to TKIs triggers resistance mechanisms and the sequential administration of other TKIs and chemotherapy is, for the most part, not targeted. In this context, extending the benefit deriving from precision medicine is paramount, above all when disease progression occurs in a limited number of sites. Retrospective data indicate that, in oligoprogressive disease, targeted therapy beyond progression combined with definitive local treatment of the progressing site(s) is an effective alternative. In these cases, multidisciplinary approach becomes essential for an integrated treatment strategy, depending on the s..... READ ARTICLE

Preprints DOI:10.20944/preprints202112.0145.v1

Authors: Pisano, C.; De Filippis, M.; Jacobs, F.; Novello, S.; Reale, M.L.

Review Paper, Pre-PrintKirk SmithDecember 9, 2021oligoprogression, NSCLC, ALK rearrangement

Modeling diverse genetic subtypes of lung adenocarcinoma with a next-generation alveolar type 2 organoid platform

Lung cancer is the leading cause of cancer-related death worldwide. Lung adenocarcinoma (LUAD), the most common histological subtype, accounts for 40% of all cases. While genetically engineered mouse models (GEMMs) recapitulate the histological progression and transcriptional evolution of human LUAD, they are slow and technically demanding. In contrast, cell line transplant models are fast and flexible, but are often derived from clonal idiosyncratic tumors that fail to capture the full spectrum of clinical disease. Organoid technologies provide a means to create next-generation cancer models that integrate the most relevant features of autochthonous and transplant-based systems, yet robust and faithful LUAD organoid platforms are currently lacking. Here, we describe optimized conditions to continuously expand murine alveolar type 2 cells (AT2), a prominent cell-of-origin for LUAD, in organoid culture. These organoids display canonical features of AT2 cells, including marker gene expre..... READ ARTICLE

bioRxiv DOI:10.1101/2021.12.07.471632

Authors: Santiago Naranjo, Christina M. Cabana, Lindsay M. LaFave, Peter M.K. Westcott, Rodrigo Romero, Arkopravo Ghosh, Laura Z. Liao, Jason M. Schenkel, Isabella Del Priore, Arjun Bhutkar, Dian Yang, Tyler Jacks

Pre-Clinical, Pre-Print, group1Kirk SmithDecember 7, 2021Lung adenocarcinoma, organoid culture

Diverse routes of Club cell evolution in lung adenocarcinoma

The high plasticity of lung epithelial cells, has for many years, confounded the correct identification of the cell-of-origin of lung adenocarcinoma (LUAD), one of the deadliest malignancies worldwide. Here, we address the cell-of-origin of LUAD, by employing lineage-tracing mouse models combined with a CRISPR/Cas9 system to induce an oncogenic Eml4-Alk rearrangement in virtually all epithelial cell types of the lung. We find that Club cells give rise to lung tumours with a higher frequency than AT2 cells. Based on whole genome methylome, we identified that tumours retain an ‘epigenetic memory’ derived from their originating cell type but also develop a tumour-specific pattern regardless of their origin. Single-cell transcriptomic analyses identified two trajectories of Club cell evolution which are similar to the ones used during lung regeneration, providing a link between lung regeneration and cancer initiation. On both routes, tumours lose their Club cell identity and gain an AT2-li..... READ ARTICLE

BioRxIV DOI:10.1101/2021.06.10.447936

Authors: Yuanyuan Chen, Reka Toth, Sara Chocarro, Dieter Weichenhan, Joschka Hey, Pavlo Lutsik, Stefan Sawall, Georgios T. Stathopoulos, Christoph Plass, Rocio Sotillo

PI3Kβ inhibition restores ALK inhibitor sensitivity in ALK-rearranged lung cancer

Study Proposes proposes PI3Kβ as a novel regulator of ALKi resistance in ALK-rearranged lung cancer cells, showing efficacy even in aggressive TP53 mutant and mesenchymal cells. Given that multiple salvage signals are activated upon resistance to ALKi, the co-targeting of PI3Kβ may provide a promising therapy option as PI3Kβ acts as a common effector of multiple salvage pathways, including EGFR, autophagy and GPCRs. Importantly, we found that co-targeting of PI3Kβ showed reduced toxicity in normal lung epithelial cells when compared with co-targeting of EGFR, possibly providing for a relatively safe clinical direction to treat ALK-rearranged tumors. READ ARTICLE

BioRxIV DOI:10.1101/2021.03.18.435801

Authors: Sarang S. Talwelkar, Mikko I. Mäyränpää, Julia Schüler, Nora Linnavirta, Annabrita Hemmes, Simone Adinolfi, Matti Kankainen, Wolfgang Sommergruber, Anna-Liisa Levonen, Jari Räsänen, Aija Knuuttila, Emmy W. Verschuren, Krister Wennerberg

Pre-Print, Pre-ClinicalKirk SmithMarch 18, 2021PI3Kβ inhibition

Targeted cancer therapy induces APOBEC fuelling the evolution of drug resistance

Targeted therapy directed against EGFR and ALK oncoproteins in lung cancer induced adaptations favoring apolipoprotein B mRNA-editing enzyme, catalytic polypeptide (APOBEC)-mediated genome mutagenesis. In human oncogenic EGFR-driven and ALK-driven lung cancers and preclinical models, EGFR or ALK inhibitor treatment induced the expression and DNA mutagenic activity of APOBEC3B via therapymediated activation of NF-kB signaling. Moreover, targeted therapy also mediated downregulation of certain DNA repair enzymes such as UNG2, which normally counteracts APOBEC-catalyzed DNA deamination events. In mutant EGFR-driven lung cancer mouse models, APOBEC3B was detrimental to tumour initiation and yet advantageous to tumour progression during EGFR targeted therapy, consistent with TRACERx data demonstrating subclonal enrichment of APOBEC-mediated mutagenesis. This study reveals how cancers adapt and drive genetic diversity in response to targeted therapy and identifies APOBEC deaminases as future targets for eliciting more durable clinical benefit to targeted cancer therapy. READ ARTICLE

BioRxIV DOI:10.1101/2020.12.18.423280

Authors: Manasi K. Mayekar, View ORCID ProfileDeborah R. Caswell, Natalie I. Vokes, Emily K. Law, Wei Wu, William Hill, Eva Gronroos, Andrew Rowan, Maise Al Bakir, Caroline E. McCoach, Collin M. Blakely, Nuri Alpay Temiz, Ai Nagano, D. Lucas Kerr, Julia K. Rotow, Franziska Haderk, Michelle Dietzen, Carlos Martinez Ruiz, Bruna Almeida, Lauren Cech, Beatrice Gini, Joanna Przewrocka, Chris Moore, Miguel Murillo, Bjorn Bakker, Brandon Rule, Cameron Durfee, Shigeki Nanjo, Lisa Tan, Lindsay K. Larson, Prokopios P. Argyris, William L. Brown, Johnny Yu, Carlos Gomez, Philippe Gui, Rachel I. Vogel, Elizabeth A. Yu, Nicholas J. Thomas, Subramanian Venkatesan, Sebastijan Hobor, Su Kit Chew, Nnennaya Kanu, Nicholas McGranahan, Eliezer M. Van Allen, Julian Downward, Reuben S. Harris, Trever G. Bivona, Charles Swanton

Pre-Clinical, Pre-PrintKirk SmithDecember 1, 2020ALK, EGFR, NFkB, APOBEC deaminases