A main limitation of therapies that selectively target kinase signalling pathways is the emergence of secondary drug resistance. Cetuximab, a monoclonal antibody that binds the extracellular domain ...of epidermal growth factor receptor (EGFR), is effective in a subset of KRAS wild-type metastatic colorectal cancers. After an initial response, secondary resistance invariably ensues, thereby limiting the clinical benefit of this drug. The molecular bases of secondary resistance to cetuximab in colorectal cancer are poorly understood. Here we show that molecular alterations (in most instances point mutations) of KRAS are causally associated with the onset of acquired resistance to anti-EGFR treatment in colorectal cancers. Expression of mutant KRAS under the control of its endogenous gene promoter was sufficient to confer cetuximab resistance, but resistant cells remained sensitive to combinatorial inhibition of EGFR and mitogen-activated protein-kinase kinase (MEK). Analysis of metastases from patients who developed resistance to cetuximab or panitumumab showed the emergence of KRAS amplification in one sample and acquisition of secondary KRAS mutations in 60% (6 out of 10) of the cases. KRAS mutant alleles were detectable in the blood of cetuximab-treated patients as early as 10 months before radiographic documentation of disease progression. In summary, the results identify KRAS mutations as frequent drivers of acquired resistance to cetuximab in colorectal cancers, indicate that the emergence of KRAS mutant clones can be detected non-invasively months before radiographic progression and suggest early initiation of a MEK inhibitor as a rational strategy for delaying or reversing drug resistance.
HER2 amplification is found in more than 15% of gastric cancers and is associated with poor clinical outcome. Lapatinib, a dual HER2 and epidermal growth factor receptor (EGFR) tyrosine kinase ...inhibitor, has shown promising in vitro results in treating HER2(+) cancer cells. However, several studies have shown that activation of alternative receptor tyrosine kinases can mediate resistance to HER-targeted therapy. Here, we investigated whether activated MET can confer resistance to lapatinib inhibition of gastric cancer cells. A panel of gastric cancer cell lines was treated with lapatinib, and we observed that cell proliferation was reduced by 70% and that the degree of HER2 amplification corresponds to sensitivity to lapatinib. Immunoblotting analysis indicated that phosphorylation of HER2, EGFR, MET, AKT, and extracellular signal-regulated kinase was inhibited by lapatinib and presumably led to cell-cycle arrest as observed with flow cytometry. Hepatocyte growth factor (HGF) activation of MET receptors rescued cells from lapatinib-induced growth inhibition by restimulating the downstream pathways and restoring normal cell-cycle progression. This rescue effect could be abrogated by inhibiting MET with PHA-665752 (a highly specific MET inhibitor) or downregulating MET expression with short interfering RNA. No synergy in growth inhibition was observed when cells were treated with a combination of lapatinib and PHA-665752. Repeat studies using insulin-like growth factor 1 and fibroblast growth factor 3 could not uniformly rescue the lapatinib-treated gastric cancer cells. In conclusion, HGF/MET-mediated resistance to lapatinib is a novel mechanism of resistance to HER2-targeted agents in gastric cancer cells. Development of inhibitors targeting multiple receptors or common downstream signaling proteins merits further investigation.
Cetuximab, an antibody targeting the epidermal growth factor receptor (EGFR), is active in colorectal cancer (CRC). However, response rates range from only 10% to 20%. Here, we investigate hepatocyte ...growth factor (HGF)-dependent mesenchymal-epithelial transition factor (MET) activation as a mediator of cetuximab resistance through signal diversification in CRC cell lines.
DiFi, GEO, and LIM1215 cells were treated with varying concentrations and combinations of EGF, HGF, cetuximab, and PHA-665752 (a highly specific MET kinase inhibitor). Biological end points included proliferation, cell cycle arrest, and apoptosis. Proliferation was measured using WST-1 assays and synergy investigated via isobolograms. Expression and signaling were examined using immunoblotting.
EGFR and MET are coexpressed in these CRC cell lines, and dual receptor activation synergistically increased proliferation. Cetuximab inhibited cell growth by 60%-80% with an associated dephosphorylation of EGFR, MAPK, and/or AKT. Addition of HGF to cetuximab-treated cells phosphorylated MET, but not EGFR or ErbB3, restimulated the MAPK and AKT pathways, restored cell proliferation, and rescued cells from G1 arrest and apoptosis. Importantly, this effect could be abrogated by inhibiting MET activation with PHA-665752 or by downregulating MET expression with RNAi.
HGF-induced MET activation is a novel mechanism of cetuximab resistance in CRC. Inhibition of the HGF-MET pathway may improve response to EGFR inhibitors in CRC, and combination therapy should be further investigated.
Modified frailty index (mFI) has been proposed as a reliable tool in predicting postoperative outcomes after surgery. This study aims to evaluate whether mFI could be utilized to predict readmissions ...after colorectal resection for patients with cancer by using nationwide cohort.
Patients undergoing elective abdominal colorectal resection for colorectal cancer were reviewed from the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) procedure-targeted database (2010–2012). A previously described mFI was calculated. Demographics, comorbidities, and 30-day postoperative complications were compared between patients who were readmitted or not after colorectal surgery.
A total of 7337 patients were identified with a mean age of 65.8(±13.6) years. Eight hundred seventy-one (11.8%) patients were readmitted at least once within 30 days. Age, gender, BMI, and other comorbidities were comparable between the groups. O approach, current smoking, mFI(>3/11), disseminating cancer, bleeding disorder and longer operative time were found to independently associated with readmission.
An 11-point modified frailty index as measured in NSQIP correlates with readmissions after colorectal resection in patients with colon and rectal cancer.
•mFI is a quick and simple tool that can predict readmissions after colorectal surgery.•Open approach, current smoking, disseminating cancer are associated with readmission.•Bleeding disorder and longer operative time are associated with readmission.
Background
Limited data on the relationship between postoperative complications (POCs) after colorectal cancer resection and oncologic outcomes are available. We hypothesized that the increased ...severity of POCs is associated with progressively worse oncologic outcomes.
Methods
Patients with pathological stages I–III colorectal adenocarcinoma undergoing elective curative resection in a single institution between 2000 and 2012 were identified from a prospectively collected database. The severity of POCs was determined using the Clavien–Dindo classification, and oncologic outcomes were assessed.
Results
Of 2266 patients, 669 (30%) had at least one POC. POCs were not associated with pathologic stage (
p
= 0.58) or use of adjuvant therapy (
p
= 0.19). With a mean follow-up of 5.3 years, POCs were associated with decreased 5-year overall survival (OS) (60% vs. 77%,
p
< 0.001), disease-free survival (DFS) (53% vs. 70%,
p
< 0.001), cancer-specific survival (CSS) (81% vs. 87%,
p
< 0.001), and increased overall recurrence rates (19% vs. 15%,
p
= 0.008). Increasing Clavien–Dindo scores from I to IV was significantly associated with progressively decreasing OS (71, 64, 60, 22%,
p
< 0.001), DFS (65, 58, 51, 19%,
p
< 0.001), CSS (88, 77, 79, 74%,
p
< 0.001), and increasing recurrence rates (12, 20, 26, 18%,
p
= 0.002). Multivariate analysis confirmed POCs as an independent factor associated with decreased OS hazard ratio (HR) 0.63, 95% CI 0.52–0.76, DFS (HR 0.64, 95% CI 0.54–0.76), CSS (HR 0.73, 95% CI 0.56–0.97), and increased recurrence rates (HR 1.36, 95% CI 1.02–1.80).
Conclusions
POCs are associated with adverse oncologic outcomes, with increasing effect with higher Clavien–Dindo score. Efforts to reduce both the incidence and severity of complications should result in improved oncologic outcomes.
Dysfunctional inflammatory pathways are associated with an increased risk of cancer, including colorectal cancer. We have previously identified and enriched for a self-renewing, colon cancer stem ...cell (CCSC) subpopulation in primary sporadic colorectal cancers (CRC) and a related subpopulation in ulcerative colitis (UC) patients defined by the stem cell marker, aldehyde dehydrogenase (ALDH). Subsequent work demonstrated that CCSC-initiated tumors are dependent on the inflammatory chemokine, CXCL8, a known inducer of tumor proliferation, angiogenesis and invasion. Here, we use RNA interference to target CXCL8 and its receptor, CXCR1, to establish the existence of a functional signaling pathway promoting tumor growth initiated by sporadic and colitis CCSCs. Knocking down either CXCL8 or CXCR1 had a dramatic effect on inhibiting both in vitro proliferation and angiogenesis. Likewise, tumorigenicity was significantly inhibited due to reduced levels of proliferation and angiogenesis. Decreased expression of cycle cell regulators cyclins D1 and B1 along with increased p21 levels suggested that the reduction in tumor growth is due to dysregulation of cell cycle progression. Therapeutically targeting the CXCL8-CXCR1 signaling pathway has the potential to block sustained tumorigenesis by inhibiting both CCSC- and pCCSC-induced proliferation and angiogenesis.
Deleterious effects of environmental exposures may contribute to the rising incidence of early-onset colorectal cancer (eoCRC). We assessed the metabolomic differences between patients with eoCRC, ...average-onset CRC (aoCRC), and non-CRC controls, to understand pathogenic mechanisms. Patients with stage I-IV CRC and non-CRC controls were categorized based on age ≤ 50 years (eoCRC or young non-CRC controls) or ≥ 60 years (aoCRC or older non-CRC controls). Differential metabolite abundance and metabolic pathway analyses were performed on plasma samples. Multivariate Cox proportional hazards modeling was used for survival analyses. All P values were adjusted for multiple testing (false discovery rate, FDR P < 0.15 considered significant). The study population comprised 170 patients with CRC (66 eoCRC and 104 aoCRC) and 49 non-CRC controls (34 young and 15 older). Citrate was differentially abundant in aoCRC vs. eoCRC in adjusted analysis (Odds Ratio = 21.8, FDR P = 0.04). Metabolic pathways altered in patients with aoCRC versus eoCRC included arginine biosynthesis, FDR P = 0.02; glyoxylate and dicarboxylate metabolism, FDR P = 0.005; citrate cycle, FDR P = 0.04; alanine, aspartate, and glutamate metabolism, FDR P = 0.01; glycine, serine, and threonine metabolism, FDR P = 0.14; and amino-acid t-RNA biosynthesis, FDR P = 0.01. 4-hydroxyhippuric acid was significantly associated with overall survival in all patients with CRC (Hazards ratio, HR = 0.4, 95% CI 0.3-0.7, FDR P = 0.05). We identified several unique metabolic alterations, particularly the significant differential abundance of citrate in aoCRC versus eoCRC. Arginine biosynthesis was the most enriched by the differentially altered metabolites. The findings hold promise in developing strategies for early detection and novel therapies.
Background
The incidence of colorectal cancer (CRC) in patients under age 50 is rising for unclear reasons. We examined the effects of socioeconomic factors on outcomes for patients with early‐onset ...CRC compared to late‐onset CRC.
Methods
Patients with CRC from 2004 to 2015 in the National Cancer Database were included and categorized by age (under or over 50 years). Differences in demographic and socioeconomic factors, disease characteristics, and survival outcomes between early‐onset versus late‐onset CRC patients were assessed by Chi‐squared test and Cox models.
Results
The study population included 1,061,204 patients, 108,058 (10.2%) of whom were under age 50. The proportion of patients diagnosed under age 50 increased over time: 9.4% in 2004–2006, 10.1% in 2007–2009, 10.5% in 2010–2012, and 10.7% in 2013–2015 (p < 0.0001). Early‐onset CRC patients were more likely to be Black (15.1% vs. 11.3%) or Hispanic (8.6% vs. 4.6%) and to present with stage 4 disease (24.9% vs. 17.0%), p < 0.0001 for all. Black patients had the worst median OS (58.3 months) compared to White (67.0 months), Hispanic (91.6 months), or Asian (104.9 months) patients, p < 0.0001. Within the subgroup of early‐onset CRC patients with private insurance, Black patients had worse OS compared to White patients, even in communities with higher income and education status.
Conclusions
Early‐onset CRC continues to increase. Patients with early‐onset CRC are more likely to be Black or Hispanic and to present with stage 4 cancer. Early‐onset Black patients showed worse OS compared to White patients in all income subgroups, even with private insurance.
Patients with early‐onset colorectal cancer are more likely to be Black or Hispanic and to present with stage 4 cancer. Within the subgroup of early‐onset CRC patients with private insurance, Black patients had worse OS compared to White patients, even in communities with higher income and education status.
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