Trastuzumab, a monoclonal antibody to human epidermal growth factor receptor 2 (HER2), has improved survival in patients with HER2-positive advanced gastric or gastroesophageal junction cancer (AGC). ...The inevitable development of resistance to trastuzumab remains a problem, however, with several treatment strategies that have proven effective in breast cancer having failed to show clinical benefit in AGC. In this review, we summarize the mechanisms underlying resistance to HER2-targeted therapy and outline past and current challenges in the treatment of HER2-positive AGC refractory to trastuzumab. We further describe novel agents such as HER2 antibody-drug conjugates that are under development and have shown promising antitumor activity in early studies.
Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate consisting of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic ...topoisomerase I inhibitor. The drug may have efficacy in patients with HER2-positive advanced gastric cancer.
In an open-label, randomized, phase 2 trial, we evaluated trastuzumab deruxtecan as compared with chemotherapy in patients with HER2-positive advanced gastric cancer. Patients with centrally confirmed HER2-positive gastric or gastroesophageal junction adenocarcinoma that had progressed while they were receiving at least two previous therapies, including trastuzumab, were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan (6.4 mg per kilogram of body weight every 3 weeks) or physician's choice of chemotherapy. The primary end point was the objective response, according to independent central review. Secondary end points included overall survival, response duration, progression-free survival, confirmed response (response persisting ≥4 weeks), and safety.
Of 187 treated patients, 125 received trastuzumab deruxtecan and 62 chemotherapy (55 received irinotecan and 7 paclitaxel). An objective response was reported in 51% of the patients in the trastuzumab deruxtecan group, as compared with 14% of those in the physician's choice group (P<0.001). Overall survival was longer with trastuzumab deruxtecan than with chemotherapy (median, 12.5 vs. 8.4 months; hazard ratio for death, 0.59; 95% confidence interval, 0.39 to 0.88; P = 0.01, which crossed the prespecified O'Brien-Fleming boundary 0.0202 on the basis of number of deaths). The most common adverse events of grade 3 or higher were a decreased neutrophil count (in 51% of the trastuzumab deruxtecan group and 24% of the physician's choice group), anemia (38% and 23%, respectively), and decreased white-cell count (21% and 11%). A total of 12 patients had trastuzumab deruxtecan-related interstitial lung disease or pneumonitis (grade 1 or 2 in 9 patients and grade 3 or 4 in 3), as adjudicated by an independent committee. One drug-related death (due to pneumonia) was noted in the trastuzumab deruxtecan group; no drug-related deaths occurred in the physician's choice group.
Therapy with trastuzumab deruxtecan led to significant improvements in response and overall survival, as compared with standard therapies, among patients with HER2-positive gastric cancer. Myelosuppression and interstitial lung disease were the notable toxic effects. (Funded by Daiichi Sankyo; DESTINY-Gastric01 ClinicalTrials.gov number, NCT03329690.).
The
mutation occurs in approximately 8% of human colorectal cancers and is associated with therapeutic resistance that is due, in part, to reactivation of MEK/ERK signaling cascade. Recently, pathway ...analysis identified cyclin-dependent kinase 1 (CDK1) upregulation in a subset of human
colorectal cancers. Therefore, it was determined whether CDK1 antagonism enhances the efficacy of MEK inhibition in
colorectal cancer cells.
colorectal cancer cell lines expressing CDK1 were sensitized to apoptosis upon siRNA knockdown or small-molecule inhibition with RO-3306 (CDK1 inhibitor) or dinaciclib (CDK1, 2, 5, 9 inhibitors). Combination of RO-3306 or dinaciclib with cobimetinib (MEK inhibitor) cooperatively enhanced apoptosis and reduced clonogenic survival versus monotherapy. Cells isogenic or ectopic for
displayed resistance to CDK1 inhibitors, as did cells with ectopic expression of constitutively active
CDK1 inhibitors induced a
-dependent apoptosis shown by caspase-8 restoration in deficient NB7 cells that enhanced dinaciclib-induced CASP3 cleavage. CDK inhibitors suppressed pro-CASP8 phosphorylation at S387, as shown by drug withdrawal, which restored p-S387 and increased mitosis. In a colorectal cancer xenograft model, dinaciclib plus cobimetinib produced significantly greater tumor growth inhibition in association with a caspase-dependent apoptosis versus either drug alone. The Cancer Genome Atlas (TCGA) transcriptomic dataset revealed overexpression of CDK1 in human colorectal cancers versus normal colon. Together, these data establish CDK1 as a novel mediator of apoptosis resistance in
colorectal cancers whose combined targeting with a MEK/ERK inhibitor represents an effective therapeutic strategy.
CDK1 is a novel mediator of apoptosis resistance in
colorectal cancers whose dual targeting with a MEK inhibitor may be therapeutically effective.
.
The
MET
protooncogene encodes the receptor tyrosine kinase c-MET (MET). Aberrant activation of MET signaling occurs in a subset of advanced malignancies, including gastric cancer, and promotes tumor ...cell growth, survival, migration, and invasion as well as tumor angiogenesis, suggesting its potential importance as a therapeutic target. MET can be activated by two distinct pathways that are dependent on or independent of its ligand, hepatocyte growth factor (HGF), with the latter pathway having been attributed mostly to
MET
amplification in gastric cancer. Preclinical evidence has suggested that interruption of the HGF–MET axis either with antibodies to HGF or with MET tyrosine kinase inhibitors (TKIs) has antitumor effects in gastric cancer cells. Overexpression of MET occurs frequently in gastric cancer and has been proposed as a potential predictive biomarker for anti-MET therapy. However, several factors can trigger such MET upregulation in a manner independent of HGF, suggesting that gastric tumors with MET overexpression are not necessarily MET driven. On the other hand, gastric cancer cells with
MET
amplification are dependent on MET signaling for their survival and are thus vulnerable to MET TKI treatment. Given the low prevalence of
MET
amplification in gastric cancer (approximately 8 %), testing for this genetic change would substantially narrow the target population but it might constitute a better biomarker than MET overexpression for MET TKI therapy. We compare aberrant MET signaling dependent on the HGF–MET axis or on
MET
amplification as well as address clinical issues and challenges associated with the identification of appropriate biomarkers for MET-driven tumors.
Comprehensive genomic profiling enables genomic biomarker detection in advanced solid tumors. Here, to evaluate the utility of circulating tumor DNA (ctDNA) genotyping, we compare trial enrollment ...using ctDNA sequencing in 1,687 patients with advanced gastrointestinal (GI) cancer in SCRUM-Japan GOZILA (no. UMIN000016343), an observational ctDNA-based screening study, to enrollment using tumor tissue sequencing in the same centers and network (GI-SCREEN, 5,621 patients). ctDNA genotyping significantly shortened the screening duration (11 versus 33 days, P < 0.0001) and improved the trial enrollment rate (9.5 versus 4.1%, P < 0.0001) without compromising treatment efficacy compared to tissue genotyping. We also describe the clonal architecture of ctDNA profiles in ~2,000 patients with advanced GI cancer, which reinforces the relevance of many targetable oncogenic drivers and highlights multiple new drivers as candidates for clinical development. ctDNA genotyping has the potential to accelerate innovation in precision medicine and its delivery to individual patients.
Colorectal cancer (CRC) is a disease in which pathogenesis is influenced by genetic and epigenetic events that occur with tumor initiation and progression. Large variation exists in individual ...patient prognosis and response to chemotherapy, caused by molecular heterogeneity. Certain biomarkers have been identified that can predict clinical outcome beyond tumor staging, and inform treatment selection. Molecular testing is routinely performed in clinical practice for the selection of patients for targeted biological agents or immunotherapy, and is advocated for prognostic stratification. Estimating prognosis can avoid undertreatment or overtreatment and also guide the intensity of patient follow-up. Classifiers of CRC have been developed that integrate genetic and/or epigenetic features. The mutational status of KRAS and BRAF(V600E) oncogenes combined with analysis of the DNA mismatch repair system with/without the CpG island methylator phenotype (CIMP) has been shown to identify colon cancer subtypes with distinct clinical features and prognoses. Gene expression profiling has also been used to subtype CRCs and can overcome the limitations of single/limited gene testing. A recent effort identified 4 consensus molecular subtypes of biological relevance that were associated with different patient outcomes. Efforts to validate and refine these subtypes to include additional genomic features are ongoing. The focus of this article is to highlight molecular markers that can inform clinical decision-making in patients with CRC.
Therapies targeted to human epidermal growth factor receptor 2 (HER2) have proven effective against tumors positive for HER2 amplification, but there is an unmet clinical need for the treatment of ...tumors that express HER2 protein in the absence of HER2 amplification. fam‐ trastuzumab deruxtecan (DS‐8201a) is a novel antibody–drug conjugate composed of the anti‐HER2 antibody and the topoisomerase I inhibitor, an exatecan derivative. It has shown efficacy against tumors that express HER2 and is currently under evaluation in clinical trials. We here show that the antitumor activity of fam‐ trastuzumab deruxtecan is dependent on the expression level of HER2 protein in colorectal cancer (CRC) cell lines negative for HER2 amplification. We established isogenic CRC cell lines that express various levels of HER2 protein in the absence of HER2 amplification, and we found that cells that express HER2 at a high level were sensitive to fam‐ trastuzumab deruxtecan but not to conventional HER2‐targeted therapies. Furthermore, fam‐ trastuzumab deruxtecan manifested a bystander killing effect both in vitro and in vivo, with cells essentially negative for HER2 expression also being killed in the presence of HER2‐expressing cells, an effect that has the potential to overcome heterogeneity of HER2 expression in CRC tumors. Our results thus suggest that fam‐ trastuzumab deruxtecan warrants further study as a potential treatment for CRC tumors that express HER2 protein in the absence of HER2 amplification.
What's new?
HER2‐targeted therapies have proven effective against tumors positive for HER2 amplification, but there is an unmet clinical need for tumors that express HER2 in the absence of HER2 amplification. fam‐ trastuzumab deruxtecan (DS‐8201a) is a novel antibody‐drug conjugate composed of the anti‐HER2 antibody and the topoisomerase I inhibitor. Here, DS‐8201a showed efficacy on colorectal cancer (CRC) cell lines that express HER2 in the absence of HER2 amplification. Furthermore, fam‐ trastuzumab deruxtecan exhibited a bystander killing effect in co‐culture models of HER2‐expressing cells and HER2‐negative cells. The results may offer a new treatment option against CRC according to HER2 expression levels.
EGFR tyrosine kinase inhibitors (TKIs) are standard therapy for EGFR-mutant non-small cell lung cancer (NSCLC); however, these tumours eventually acquire chemoresistance. U3-1402 is an anti-HER3 ...antibody-drug conjugate with a novel topoisomerase I inhibitor, DXd. In the current study, we evaluated the anticancer efficacy of U3-1402 in EGFR-mutant NSCLC cells with acquired resistance to EGFR-TKIs. HCC827GR5 and PC9AZDR7 are EGFR-TKI-resistant clones for gefitinib and osimertinib, respectively. U3-1402 alone or in combination with the EGFR-TKI erlotinib demonstrated potent anticancer efficacy in HCC827GR5 cells using an in vitro growth inhibition assay and in vivo xenograft mouse model. U3-1402 induced apoptosis in HCC827GR5 cells accompanying phosphorylation of histone H2A.X, a marker of DNA damage, but did not block HER3/PI3K/AKT signalling. Further, we found using flow cytometry that the cell surface HER3 expression level in HCC827GR5 cells was twice that found in HCC827 cells, indicating internalization of U3-1402 was increased in resistant cells. In addition, administration of U3-1402 notably repressed growth of EGFR-TKI osimertinib-resistant PC9AZDR7 xenograft tumours, and that PC9AZDR7 cells expressed five times greater cell surface HER3 than PC9 cells. Furthermore, using immunofluorescent microscopy, HER3 was observed predominantly in the nucleus of PC9 cells, but was localized in the cytoplasm of PC9AZDR7 cells. This finding indicates that altered trafficking of the HER3-U3-1402 complex may accelerate linker payload cleavage by cytoplasmic lysosomal enzymes, resulting in DNA damage. Our results indicate that administration of U3-1402 alone or in combination with an EGFR-TKI may have potential as a novel therapy for EGFR-TKI-resistant EGFR-mutant NSCLC.
The efficacy of programmed cell death–1 (PD‐1) blockade in patients with non–small cell lung cancer (NSCLC) positive for epidermal growth factor receptor (EGFR) gene mutations has been found to be ...limited, but the underlying mechanisms for this poor response have remained obscure. Given that the recognition by T cells of tumor antigens presented by major histocompatibility complex class I (MHC‐I) molecules is essential for an antitumor immune response, we examined the effects of EGFR tyrosine kinase inhibitors (TKIs) on MHC‐I expression in NSCLC cell lines. Appropriate EGFR‐TKIs increased MHC‐I expression at the mRNA and cell surface protein levels in NSCLC cells positive for EGFR mutations including those with the T790M secondary mutation. Trametinib, an inhibitor of the extracellular signal–regulated kinase (ERK) kinase MEK, also increased MHC‐I expression, whereas the phosphatidylinositol 3‐kinase (PI3K) inhibitor buparlisib did not, suggesting that the MEK‐ERK pathway mediates the down‐regulation of MHC‐I expression in response to EGFR activation. Immunohistochemical analysis of EGFR‐mutated NSCLC specimens obtained before and after EGFR‐TKI treatment also revealed down‐regulation of phosphorylated forms of EGFR and ERK in association with up‐regulation of MHC‐I, an increased number of infiltrating CD8+ T cells, and increased PD‐1 ligand 1 expression after such treatment. Our results thus suggest that mutational activation of EGFR inhibits MHC‐I expression through the MEK‐ERK pathway in NSCLC and thereby contributes to the poor response of such tumors to immunotherapy. Further studies are warranted to evaluate the relation between EGFR‐MEK‐ERK signaling in and the immune response to EGFR‐mutated NSCLC.
Mutational activation of EGFR inhibits MHC‐I expression through the MEK‐ERK pathway in NSCLC and thereby may contribute to the poor response of such tumors to immunotherapy.
PDF
![[fam‐] trastuzumab deruxtec...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/0020-7136_1097-0215/small "[fam‐] trastuzumab deruxtecan, antitumor activity is dependent on HER2 expression level rather than on HER2 amplification")
