Receptor tyrosine kinases (RTKs) are key regulatory signaling proteins governing cancer cell growth and metastasis. During the last two decades, several molecules targeting RTKs were used in oncology as a first or second line therapy in different types of cancer. However, their effectiveness is limited by the appearance of resistance or adverse effects. In this review, we summarize the main features of RTKs and their inhibitors (RTKIs), their current use in oncology, and mechanisms of resistance. We also describe the technological advances of artificial intelligence, chemoproteomics, and microfluidics in elaborating powerful strategies that could be used in providing more efficient and selective small molecules inhibitors of RTKs. Finally, we discuss the interest of therapeutic combination of different RTKIs or with other molecules for personalized treatments, and the challenge for effective combination with less toxic and off-target effects.

BACKGROUND: With the emergence of the tumor microenvironment as an essential ingredient of cancer malignancy, therapies targeting the host compartment of tumors have begun to be designed and applied in the clinic. CONTENT: The malignant features of cancer cells cannot be manifested without an important interplay between cancer cells and their local environment. The tumor infiltrate composed of immune cells, angiogenic vascular cells, lymphatic endothelial cells, and cancer-associated fibroblastic cells contributes actively to cancer progression. The ability to change these surroundings is an important property by which tumor cells are able to acquire some of the hallmark functions necessary for tumor growth and metastatic dissemination. Thus in the clinical setting the targeting of the tumor microenvironment to encapsulate or destroy cancer cells in their local environment has become mandatory. The variety of stromal cells, the complexity of the molecular components of the tumor stroma, and the similarity with normal tissue present huge challenges for therapies targeting the tumor microenvironment. These issues and their interplay are addressed in this review. After a decade of intensive clinical trials targeting cellular components of the tumor microenvironment, more recent investigations have shed light on the important role in cancer progression played by the noncellular stromal compartment composed of the extracellular matrix. SUMMARY: A better understanding of how the tumor environment affects cancer progression should provide new targets for the isolation and destruction of cancer cells via interference with the complex crosstalk established between cancer cells, host cells, and their surrounding extracellular matrix.

Tumor recurrence is a major clinical issue that represents the principal cause of cancer-related deaths, with few targetable common pathways. Mechanisms by which residual tumors persist and progress under a continuous shift between hypoxia-reoxygenation after neoadjuvent-therapy are unknown. In this study, we investigated the role of lipid metabolism and tumor redox balance in tumor recurrence. Lipidomics, proteomics and mass spectrometry imaging approaches where applied to mouse tumor models of recurrence. Genetic and pharmacological inhibitions of lipid mediators in tumors were used in vivo and in functional assays in vitro. We found that stearoyl-CoA desaturase-1 (SCD1) expressed by cancer cells and fatty acid binding protein-4 (FABP4) produced by tumor endothelial cells (TECs) and adipocytes in the tumor microenvironment (TME) are essential for tumor relapse in response to tyrosine kinase inhibitors (TKI) and chemotherapy. SCD1 and FABP4 were also found upregulated in recurrent human breast cancer samples and correlated with worse prognosis of cancer patients with different types of tumors. Mechanistically, SCD1 leads to fatty acid (FA) desaturation and FABP4 derived from TEM enhances lipid droplet (LD) in cancer cells, which cooperatively protect from oxidative stress-induced ferroptosis. We revealed that lipid mobilization and desaturation elicit tumor intrinsic antioxidant and anti-ferroptotic resources for survival and regrowth in a harsh TME. Inhibition of lipid transport from TME by FABP4 inhibitor reduced tumor regrowth and by genetic - or by pharmacological - targeting SCD1 in vivo, tumor regrowth was abolished completely. This finding unveils that it is worth taking advantage of tumor lipid addiction, as a tumor vulnerability to design novel treatment strategy to prevent cancer recurrence.