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•There are approved targeted drugs for NSCLCs carrying EGFR, BRAF and MET mutations.•NSCLC testing guidelines include the analysis of ALK, ROS1, RET and NTRK gene fusions.•NSCLC ...emerging targets are KRAS G12C substitutions and HER2 mutations and amplifications.•The above markers can be analysed by DNA/RNA analysis, while PD-L1 testing requires IHC.•There is a paucity of predictive markers for squamous NSCLC and for cytotoxic therapy.
Molecular testing has become a mandatory component of the non-small cell lung cancer (NSCLC) management. The detection of EGFR, BRAF and MET mutations as well as the analysis of ALK, ROS1, RET and NTRK translocations have already been incorporated in the NSCLC diagnostic standards, and the inhibitors of these kinases are in routine clinical use. There are emerging biomarkers, e.g., KRAS G12C substitutions and HER2 activating alterations, which are likely to enter NSCLC guidelines upon the approval of the corresponding drugs. In addition to genetic examination, NSCLCs are usually subjected to the analysis of PD-L1 protein expression in order to direct the use of immune checkpoint inhibitors. Comprehensive NSCLC testing for multiple predictive markers requires the analysis of distinct biological molecules (DNA, RNA, proteins) and, therefore, the involvement of different analytical platforms (PCR, DNA sequencing, immunohistochemistry, FISH). There are ongoing efforts aimed at the integration of multiple NSCLC molecular assays into a single diagnostic pipeline.
Mechanisms of acquired tumor drug resistance Aleksakhina, Svetlana N.; Kashyap, Aniruddh; Imyanitov, Evgeny N.
Biochimica et biophysica acta. Reviews on cancer,
12/2019, Letnik:
1872, Številka:
2
Journal Article
Recenzirano
Systemic therapy often results in the reduction of tumor size but rarely succeeds in eradicating all cancer cells. Drug efflux, persistence of cancer stem cells (CSCs), epithelial-mesenchymal ...transition (EMT) and down-regulation of apoptosis are the most known general causes of therapy failure. Tumor escape from targeted compounds often involves pathway-specific mechanisms, which result in the restoration of the affected signaling cascade. The acquisition of drug resistance is mediated by mutations, changes in gene expression, alternative splicing, post-translational protein modifications, etc. Development of resistance to therapy may not necessary involve the emergence of new tumor clones: multiple studies demonstrate that even chemonaive neoplasms already have a small population of cells, which are capable of surviving therapeutic pressure and facilitating the disease progression. Use of combinations of cancer drugs, sequential therapy, adaptive therapy and topical ablation of drug-resistant malignant lumps may help to prolong the time to treatment failure. Many studies on mechanisms of drug resistance rely on the use of cell cultures and animal models. The development of approaches that allow efficient monitoring of the evolution of tumor phenotype in clinical setting presents a challenge.
The administration of many cancer drugs is tailored to genetic tests. Some genomic events, e.g., alterations of EGFR or BRAF oncogenes, result in the conformational change of the corresponding ...proteins and call for the use of mutation-specific compounds. Other genetic perturbations, e.g., HER2 amplifications, ALK translocations or MET exon 14 skipping mutations, cause overproduction of the entire protein or its kinase domain. There are multilocus assays that provide integrative characteristics of the tumor genome, such as the analysis of tumor mutation burden or deficiency of DNA repair. Treatment planning for non-small cell lung cancer requires testing for EGFR, ALK, ROS1, BRAF, MET, RET and KRAS gene alterations. Colorectal cancer patients need to undergo KRAS, NRAS, BRAF, HER2 and microsatellite instability analysis. The genomic examination of breast cancer includes testing for HER2 amplification and PIK3CA activation. Melanomas are currently subjected to BRAF and, in some instances, KIT genetic analysis. Predictive DNA assays have also been developed for thyroid cancers, cholangiocarcinomas and urinary bladder tumors. There is an increasing utilization of agnostic testing which involves the analysis of all potentially actionable genes across all tumor types. The invention of genomically tailored treatment has resulted in a spectacular improvement in disease outcomes for a significant portion of cancer patients.
Widespread use of the next-generation sequencing (NGS) technologies revealed that a significant percentage of tumors in children develop as a part of monogenic hereditary diseases. Predisposition to ...the development of pediatric neoplasms is characteristic of a wide range of conditions including hereditary tumor syndromes, primary immunodeficiencies, RASopathies, and phakomatoses. The mechanisms of tumor molecular pathogenesis are diverse and include disturbances in signaling cascades, defects in DNA repair, chromatin remodeling, and microRNA processing. Timely diagnosis of tumor-associated syndromes is important for the proper choice of cancer treatment, genetic counseling of families, and development of the surveillance programs. The review describes the spectrum of neoplasms characteristic of the most common syndromes and molecular pathogenesis of these diseases.
Highlights • Ovarian carcinomas arising in BRCA1/2 germ-line mutation carriers show high sensitivity to platinum-based neoadjuvant therapy. • Chemonaive hereditary ovarian cancers frequently ...demonstrate somatic loss of the wild-type BRCA1 allele. • Platinum therapy results in a rapid selection of tumor cell clones with restored heterozygous BRCA1 status.
Tumors arising in BRCA1/2 germline mutation carriers usually demonstrate somatic loss of the remaining BRCA1/2 allele and increased sensitivity to platinum compounds, anthracyclines, mitomycin C and ...poly (ADP-ribose) polymerase inhibitors (PARPi). Exposure to conventional platinum-based therapy or PARPi results in the restoration of BRCA1/2 function and development of resistance to systemic therapy, therefore, there is a need for other treatment options. Some studies suggested that the use of specific drug combinations or administration of high-dose chemotherapy may result in pronounced tumor responses. BRCA1/2-driven tumors are characterized by increased immunogenicity; promising efficacy of immune therapy has been demonstrated in a number of preclinical and clinical investigations. There are outstanding issues, which require further consideration. Platinum compounds and PARPi have very similar mode of antitumor action and are likely to render cross-resistance to each other, so their optimal position in cancer treatment schemes may be a subject of additional studies. Sporadic tumors with somatically acquired inactivation of BRCA1/2 or related genes resemble hereditary neoplasms with regard to the spectrum of drug sensitivity; the development of user-friendly BRCAness tests presents a challenge. Many therapeutic decisions are now based on the BRCA1/2 status, so the significant reduction of the turn-around time for predictive laboratory assays is of particular importance.
There are multiple applications of molecular tests in clinical oncology. Mutation analysis is now routinely utilized for the diagnosis of hereditary cancer syndromes. Healthy carriers of ...cancer-predisposing mutations benefit from tight medical surveillance and various preventive interventions. Cancers caused by germ-line mutations often require significant modification of the treatment strategy. Personalized selection of cancer drugs based on the presence of actionable mutations has become an integral part of cancer therapy. Molecular tests underlie the administration of EGFR, BRAF, ALK, ROS1, PARP inhibitors as well as the use of some other cytotoxic and targeted drugs. Tumors almost always shed their fragments (single cells or their clusters, DNA, RNA, proteins) into various body fluids. So-called liquid biopsy, i.e., the analysis of circulating DNA or some other tumor-derived molecules, holds a great promise for non-invasive monitoring of cancer disease, analysis of drug-sensitizing mutations and early cancer detection. Some tumor- or tissue-specific mutations and expression markers can be efficiently utilized for the diagnosis of cancers of unknown primary origin (CUPs). Systematic cataloging of tumor molecular portraits is likely to uncover a multitude of novel medically relevant DNA- and RNA-based markers.
Many tumors have well-defined vulnerabilities, thus potentially allowing highly specific and effective treatment. There is a spectrum of actionable genetic alterations which are shared across various ...tumor types and, therefore, can be targeted by a given drug irrespective of tumor histology. Several agnostic drug-target matches have already been approved for clinical use, e.g., immune therapy for tumors with microsatellite instability (MSI) and/or high tumor mutation burden (TMB), NTRK1-3 and RET inhibitors for cancers carrying rearrangements in these kinases, and dabrafenib plus trametinib for
V600E mutated malignancies. Multiple lines of evidence suggest that this histology-independent approach is also reasonable for tumors carrying
and
translocations, biallelic
inactivation and/or homologous recombination deficiency (HRD), strong
amplification/overexpression coupled with the absence of other MAPK pathway-activating mutations, etc. On the other hand, some well-known targets are not agnostic: for example, PD-L1 expression is predictive for the efficacy of PD-L1/PD1 inhibitors only in some but not all cancer types. Unfortunately, the individual probability of finding a druggable target in a given tumor is relatively low, even with the use of comprehensive next-generation sequencing (NGS) assays. Nevertheless, the rapidly growing utilization of NGS will significantly increase the number of patients with highly unusual or exceptionally rare tumor-target combinations. Clinical trials may provide only a framework for treatment attitudes, while the decisions for individual patients usually require case-by-case consideration of the probability of deriving benefit from agnostic versus standard therapy, drug availability, associated costs, and other circumstances. The existing format of data dissemination may not be optimal for agnostic cancer medicine, as conventional scientific journals are understandably biased towards the publication of positive findings and usually discourage the submission of case reports. Despite all the limitations and concerns, histology-independent drug-target matching is certainly feasible and, therefore, will be increasingly utilized in the future.
Chemotherapy constitutes the backbone of cancer treatment. Several predictive assays assist personalized administration of cytotoxic drugs and are recommended for use in a clinical setting. The ...deficiency of DNA repair by homologous recombination (HRD), which is caused by inactivation of BRCA1/2 genes or other genetic events, is associated with high tumor responsiveness to platinum compounds, bifunctional alkylating agents and topoisomerase II poisons. Low activity of MGMT predicts the efficacy of nitrosoureas and tetrazines. Some clinically established pharmacogenetic tests allow for the adjustment of drug dosage, for example, the analysis of DPYD allelic variants for administration of fluoropyrimidines and UGT1A1 genotyping for the use of irinotecan. While there are promising molecular predictors of tumor sensitivity to pemetrexed, gemcitabine and taxanes, they remain in the investigational stage and require additional validation. Comprehensive molecular analysis of tumors obtained from drug responders and non-responders is likely to reveal new clinically useful predictive markers for cytotoxic therapy.
•Homologous recombination deficiency (HRD) can be caused by BRCA1/2 inactivation or other genetic events.•HRD renders tumor sensitivity to platinum drugs, bifunctional alkylating agents and topoisomerase II poisons.•DPYD genotyping helps avoiding fatal adverse effects from fluoropyrimidines.•UGT1A1 genotyping supports dosage adjustment for irinotecan.•There are several other promising predictive tests, which require additional validation.
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