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- 2018
Personalized medicine: exploiting druggable vulnerabilities for KRAS-driven lung cancerKeywords: lung cancer, KRAS, galectin-3, macropinocytosis, integrin Abstract: Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers and remains the leading cause of cancer-related death in the world [1]. Traditional cytotoxic chemotherapeutic agents have shown only very limited benefits for patients suffering from this type of cancer, highlighting the need for determining molecular drivers of NSCLC. Insights into molecular pathogenesis of lung cancers have identified mutations in specific genes involved in tumor initiation and progression. Among those, mutations in the Kirsten rat sarcoma (KRAS) oncogene represent one of the most prevalent genetic alterations in NSCLC. Not only KRAS mutant promotes stem like phenotype, cell proliferation, metabolic reprogramming and adaptation to the tumor microenvironment, it is also a marker of tumor aggressiveness and drug resistance [2, 3]. Therefore, KRAS has become the public enemy number one of oncologists and researchers, who have been working tirelessly to conceive therapeutic strategies aiming at interfering with its many functions. However, despite multiple approaches developed so far to interfere with mutant KRAS, its downstream signaling or its synthetic lethal vulnerabilities, and besides recent progress in targeting specifically KRAS G12C mutant, most strategies have failed in clinic due to compensatory mechanisms, alternative pathways, undesirable nonspecific effects, high drug toxicity and tumor heterogeneity. Indeed, one important obstacle in KRAS signaling inhibition strategies is the inter-and intra-tumor heterogeneity. One idea of personalized cancer therapy is to identify specific subgroups of cancer patients that will benefit from specific therapeutic strategies. Therefore, finding druggable target molecules to inhibit oncogenic KRAS signaling and identification of predictive biomarkers are key challenges in lung cancer therapy and more generally in cancer research
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