profiling-sensitivity-to-targeted-therapies-egfr-mutant-nsclc-patient

Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids

Novel 3D cancer organoid cultures derived from clinical patient specimens represent an important model system to evaluate intratumor heterogeneity and ...

University of California, San Francisco

Anaplastic lymphoma kinase () gene rearrangements have been identified in lung cancer at 3-7% frequency, thus representing an important subset of genetic lesions that drive oncogenesis in this disease. Despite the availability of multiple FDA-approved small molecule inhibitors targeting ALK fusion proteins, drug resistance to ALK kinase inhibitors is a common problem in clinic. Thus, there is an unmet need to deepen the current understanding of genomic characteristics of ALK rearrangements and to develop novel therapeutic strategies that can overcome ALK inhibitor resistance. In this review, we present the genomic landscape of ALK fusions in the context of co-occurring mutations with other cancer-related genes, pointing to the central role of genetic epistasis (gene-gene interactions) in ALK-driven advanced-stage lung cancer. We discuss the possibility of targeting druggable domains within ALK fusion partners in addition to available strategies inhibiting the ALK kinase domain directly. Finally, we examine the potential of targeting ALK fusion-specific neoantigens in combination with other treatments, a strategy that could open a new avenue for the improved treatment of ALK positive lung cancer patients.

Non-Canonical Thinking for Targeting ALK-Fusion Onco-Proteins in Lung Cancer.

The nonreceptor protein tyrosine phosphatase SHP2 (encoded by PTPN11) integrates growth and differentiation signals from receptor tyrosine kinases (RTKs) into the RAS/mitogen-activated protein kinase (MAPK) cascade. Considered 'undruggable' over three decades, SHP2 is now a potentially druggable target with the advent of allosteric SHP2 inhibitors. These agents hold promise for improving patient outcomes, showing efficacy in preclinical cancer models, where SHP2 is critical for either oncogenic signaling or resistance to current targeted agents. SHP2 inhibition may also produce immunomodulatory effects in certain tumor microenvironment cells to help cultivate antitumor immune responses. The first generation of allosteric SHP2 inhibitors is under clinical evaluation to determine safety, appropriate tolerability management, and antitumor efficacy, investigations that will dictate future clinical applications.

Article	Year
Non-Canonical Thinking for Targeting ALK-Fusion Onco-Proteins in Lung Cancer. Cancers\| PubMed ID: 29189709	2017
Allosteric SHP2 inhibitors in cancer: Targeting the intersection of RAS, resistance, and the immune microenvironment. Current opinion in chemical biology\| PubMed ID: 33418513	2021

Franziska Haderk

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