Tyrosine Kinase Receptors in Oncology Esteban-Villarrubia, Jorge; Soto-Castillo, Juan José; Pozas, Javier ...
International journal of molecular sciences,
11/2020, Letnik:
21, Številka:
22
Journal Article
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Tyrosine kinase receptors (TKR) comprise more than 60 molecules that play an essential role in the molecular pathways, leading to cell survival and differentiation. Consequently, genetic alterations ...of TKRs may lead to tumorigenesis and, therefore, cancer development. The discovery and improvement of tyrosine kinase inhibitors (TKI) against TKRs have entailed an important step in the knowledge-expansion of tumor physiopathology as well as an improvement in the cancer treatment based on molecular alterations over many tumor types. The purpose of this review is to provide a comprehensive review of the different families of TKRs and their role in the expansion of tumor cells and how TKIs can stop these pathways to tumorigenesis, in combination or not with other therapies. The increasing growth of this landscape is driving us to strengthen the development of precision oncology with clinical trials based on molecular-based therapy over a histology-based one, with promising preliminary results.
•RET proto-oncogene represents an important driver mutation in differentiated thyroid cancer.•RET inhibitors are changing the medical management in differentiated thyroid cancer.•Resistance mechanism ...are divided in primary and acquired principally, with differences in clinical management.•Novel RET inhibitors are designed in order to revert resistance to first generation inhibitors.
Thyroid cancer is the most frequently diagnosed endocrine malignancy, with an increasing incidence over the last decades. The recent advances in understanding the molecular mechanisms underlying the carcinogenesis of thyroid cancer have led to a better therapeutic approach of these tumors. This has allowed the development and approval of several drugs during the past decade. The rearranged during transfection RET protooncogene encodes a transmembrane receptor tyrosine kinase, which is activated by chromosomal rearrangements or point mutations in multiple malignancies, including thyroid cancer. Selective RET inhibitors have proved their value in the treatment algorithm in molecularly selected patients with significantly high response rates and duration of response. Notwithstanding, there are patients who experiment rapid progression or tumor recurrence after an early response to those targeted therapies, which suggest the existence of primary and acquired mechanisms of resistance that have been largely unknown to date. In the present review, we attempt to provide a comprehensive analysis of the most relevant mechanisms of resistance to RET inhibitors which could help in the development of next generation MKI and RET inhibitors, along with combination strategies with different targeted therapies that could potentially overcome these resistances.
Immunotherapy has demonstrated a role in the therapeutic landscape of a small subset of patients with colorectal carcinoma (CRC) that harbor a microsatellite instability (MSI-H) status due to a ...deficient DNA mismatch repair (dMMR) system. The remarkable responses to immune checkpoint inhibitors (ICIs) are now being tested in the neoadjuvant setting in localized CRC, where the dMMR/MSI-H status can be found in up to 15% of patients, with remarkable results obtained in NICHE2 and 3 trials, among others. This case series aims to report our experience at a tertiary center and provide a comprehensive analysis of the possible questions and challenges to overcome if ICIs were established as standard of care in a neoadjuvant setting, as well as the potential role they may have as conversion therapy not only in locoregional advanced CRC but also in oligometastatic disease.
Colorectal cancer (CRC) is the third most frequent cancer and the second most common cause of cancer-related death in Europe. High microsatellite instability (MSI-H) due to a deficient DNA mismatch ...repair (dMMR) system can be found in 5% of metastatic CRC (mCRC) and has been established as a biomarker of response to immunotherapy in these tumors. Therefore, immune checkpoint inhibitors (ICIs) in mCRC with these characteristics were evaluated with results showing remarkable response rates and durations of response. The majority of mCRC cases have high levels of DNA mismatch repair proteins (pMMR) with consequent microsatellite stability or low instability (MSS or MSI-low), associated with an inherent resistance to ICIs. This review aims to provide a comprehensive analysis of the possible approaches to overcome the mechanisms of resistance and evaluates potential biomarkers to establish the role of ICIs in pMMR/MSS/MSI-L (MSS) mCRC.
Thyroid cancer represents a heterogenous disease whose incidence has increased in the last decades. Although three main different subtypes have been described, molecular characterization is ...progressively being included in the diagnostic and therapeutic algorithm of these patients. In fact, thyroid cancer is a landmark in the oncological approach to solid tumors as it harbors key genetic alterations driving tumor progression that have been demonstrated to be potential actionable targets. Within this promising and rapid changing scenario, current efforts are directed to improve tumor characterization for an accurate guidance in the therapeutic management. In this sense, it is strongly recommended to perform tissue genotyping to patients that are going to be considered for systemic therapy in order to select the adequate treatment, according to recent clinical trials data. Overall, the aim of this article is to provide a comprehensive review on the molecular biology of thyroid cancer focusing on the key role of tyrosine kinases. Additionally, from a clinical point of view, we provide a thorough perspective, current and future, in the treatment landscape of this tumor.
Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype arising from renal cell carcinomas. This tumor is characterized by a predominant angiogenic and immunogenic ...microenvironment that interplay with stromal, immune cells, and tumoral cells. Despite the obscure prognosis traditionally related to this entity, strategies including angiogenesis inhibition with tyrosine kinase inhibitors (TKIs), as well as the enhancement of the immune system with the inhibition of immune checkpoint proteins, such as PD-1/PDL-1 and CTLA-4, have revolutionized the treatment landscape. This approach has achieved a substantial improvement in life expectancy and quality of life from patients with advanced ccRCC. Unfortunately, not all patients benefit from this success as most patients will finally progress to these therapies and, even worse, approximately 5 to 30% of patients will primarily progress. In the last few years, preclinical and clinical research have been conducted to decode the biological basis underlying the resistance mechanisms regarding angiogenic and immune-based therapy. In this review, we summarize the insights of these molecular alterations to understand the resistance pathways related to the treatment with TKI and immune checkpoint inhibitors (ICIs). Moreover, we include additional information on novel approaches that are currently under research to overcome these resistance alterations in preclinical studies and early phase clinical trials.
Novel Tyrosine Kinase Targets in Urothelial Carcinoma Torres-Jiménez, Javier; Albarrán-Fernández, Víctor; Pozas, Javier ...
International journal of molecular sciences,
01/2021, Letnik:
22, Številka:
2
Journal Article
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Urothelial carcinoma represents one of the most prevalent types of cancer worldwide, and its incidence is expected to grow. Although the treatment of the advanced disease was based on chemotherapy ...for decades, the developments of different therapies, such as immune checkpoint inhibitors, antibody drug conjugates and tyrosine kinase inhibitors, are revolutionizing the therapeutic landscape of this tumor. This development coincides with the increasing knowledge of the pathogenesis and genetic alterations in urothelial carcinoma, from the non-muscle invasive setting to the metastatic one. The purpose of this article is to provide a comprehensive review of the different tyrosine kinase targets and their roles in the therapeutic scene of urothelial carcinoma.
BackgroundImmune checkpoint inhibitors (ICIs) have become a revolution in the treatment of many tumoral diseases, resulting in a significant increase in terms of life expectancy and quality of ...life.Despite these outstanding advances in long-life survival, a new spectrum of adverse events has been developed and is known to be one of the biggest challenges in clinical practice nowadays.Immune-mediated neurotoxicity stands out as a rather unusual complication, but its potentially lethal consequences make the characterization and right management of this adverse event a crucial issue in this field.MethodsThis is a retrospective study including all the cancer patients that have developed any neurological adverse event related to ICIs treatment, in a period of 4 years (from 2017 to 2020).Results13 patients were included in the study (8 were treated with antiPD-1/PD-L1 immunotherapy, 1 with antiCTLA-4 and 4 with the combination of both strategies). 4 patients developed generalized myasthenia gravis (GMG), 4 immune-mediated encephalitis (IME), 3 immune-related encephalopathy without radiological/analytical evidence of encephalitis, 1 mixed-polyneuropathy, and 1 polymyositis.3 patients with GMG were seropositive, 3 developed the clinical feature within the first 21 days of immunotherapy treatment and all of them received anti-PD-1/PD-L1 treatment. All patients with IME showed pleocytosis in cerebrospinal fluid, without any data in brain MRI.12 patients suspended ICIs treatment after the event and were treated with high doses of intravenous corticosteroids. Half of them required treatment with intravenous immunoglobulins. 10 showed total or partial resolution as clinical outcome. However, 4 patients passed away due to toxicity (2 with GMG). In severe cases that precise ICU admission, 4 out of 6 patients (66%) showed a spectacular clinical improvement with complete recovery after early treatment with high doses of methylprednisolone and intravenous immunoglobulins.ICIs withdrawal was sustained indefinitely in all patients, showing a progression-free survival at six-months of 50%. In patients with tumoral diseases that have an indication of treatment with ICIs, the PFS at 6 and 12 months stands at 66%.ConclusionsIn this series, the majority of neurotoxicity was related to anti-PD1/PD-L1 treatment, appearing in the first 21 days within the treatment. Most of the patients showed a favourable clinical outcome. In severe cases, an improvement in clinical features was objective after an early onset of treatment with high doses of intravenous corticosteroids and immunoglobulins.ICIs withdrawal did not suppose harm in terms of PFS in patients with tumoral types where ICIs are already indicated.
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