Time to reposition sulfonylureas in type 2 diabetes management in Indian context: A pragmatic practical approach.

Sulfonylureas (SU) continue to be a vital therapeutic category of oral hypoglycemic agents (OHAs) for the management of type 2 diabetes mellitus (T2DM). Physicians consider modern SU (gliclazide and glimepiride) as "safe and smart" choices for T2DM management. The presence of multiple international guidelines and scarcity of a national guideline may contribute to the challenges faced by few physicians in choosing the right therapeutic strategy. The role of SU in diabetes management is explicit, and the present consensus aims to emphasize the benefits and reposition SU in India. This pragmatic, practical approach aims to define expert recommendations for the physicians to improve caregivers' knowledge of the management of T2DM, leading to superior patient outcomes.

Pharmacokinetic Similarity between Biosimilar Insulin Aspart Premix SAR341402 Mix 70/30 and Originator Insulin Aspart Mix 70/30 (NovoMix 30) in Indian Adults with Type 2 Diabetes: GEMELLI M Substudy.

Background: We compared the pharmacokinetic exposure, efficacy, safety and immunogenicity of biosimilar insulin aspart premix SAR341402 Mix 70/30 (SARAsp-Mix) with its originator NovoMix® 30 insulin aspart mix (NN-Mix) in adults with type 2 diabetes. Methods: This was a randomized, open-label, parallel-group, substudy of the phase 3 GEMELLI M trial performed in three Indian centres. Totally 13 Indian participants previously treated with premix insulin received a single subcutaneous 0.3 U/kg dose of each treatment and underwent pharmacokinetic sampling for 16 h after dosing. Participants were then treated for 26 weeks as per the main GEMELLI M trial with efficacy, safety and immunogenicity compared between groups. Results: The extent of exposure (area under the plasma concentration-time curve and maximum insulin aspart concentration) to SAR341402 insulin aspart in SARAsp-Mix and to insulin aspart in NN-Mix was similar following single doses of the allocated treatment. After 26 weeks, the mean ± SD [median] change in HbA1c from baseline was similar in both treatment groups (SARAsp-Mix -0.38% ± 1.54 [-1.00%]; NN-Mix -0.18% ± 1.97 [-0.80%]). Other efficacy endpoints, insulin dosages, anti-insulin aspart antibody response, hypoglycemia and adverse events were similar between groups. Conclusions: Our results support the findings from previous studies, that SARAsp-Mix has a similar pharmacokinetic profile to NN-Mix and provides effective glycemic control with similar safety and immunogenicity profile in Indian adults with type 2 diabetes.

Rising cost of insulin: A deterrent to compliance in patients with diabetes mellitus.

BACKGROUND AND AIMS: The rapid increase in burden of type 2 diabetes mellitus (T2DM), poses a huge medico-economic challenge, especially when the cost of care is funded by out-of-pocket expenses. The aim of this review is to highlight various issues associated with rising cost of insulin, prevalence of cost-related insulin underuse, insulin related cost-saving behaviors, and viable solutions for the benefit of patients with T2DM receiving insulin. METHODS: Electronic databases (PubMed and Google Scholar) from 2000 to 2020 were searched using the key terms uncontrolled diabetes mellitus, insulin therapy, glycemic control, direct cost, indirect cost, out-of-pocket expenses, cost-related insulin underuse, cost-saving behaviors, and biosimilar insulin in developed countries and India. RESULTS: In majority of the patients with T2DM on monotherapy, addition of another oral antidiabetic agent is required. Despite these measures, the target glycemic goals are not achieved in majority of the patients resulting in various complications. These complications can be prevented and target glycemic goals can be achieved with early initiation of insulin therapy. However, rising cost is a major deterrent to the lifelong use of insulin. This results in non-compliance and further deterioration of glycemic control. Recently, biosimilar insulins have revolutionized the management of T2DM and look promising from the economic point of view. CONCLUSIONS: Biosimilar insulins are likely to further enhance the compliance of patients and should be used whenever feasible in patients with DM. However, the patient, along with prescriber should be allowed to make shared, informed decisions regarding the insulin they wish to use.

Efficacy, Safety, and Immunogenicity of Biosimilar Insulin Aspart Premix SAR341402 Mix 70/30 Compared with Originator Insulin Aspart Mix 70/30 in Adults with Diabetes (GEMELLI M): A Subgroup Analysis by Prior Type of Premix Insulin.

INTRODUCTION: We compared the efficacy, safety, and immunogenicity of biosimilar insulin aspart premix SAR341402 Mix 70/30 (70% intermediate SAR341402 protamine and 30% rapid SAR341402 solution) (SARAsp-Mix) with its originator NovoMix 30 insulin aspart mix (NN-Mix) in adults with type 1 or type 2 diabetes switching from different premix insulin analogs. METHODS: This phase 3, randomized, open-label, multinational, 26-week trial (GEMELLI M) enrolled 402 participants with type 1 or type 2 diabetes. At randomization, participants switched from their prestudy premix insulin NovoMix 30 (n = 341) or Humalog Mix 25/Liprolog Mix 25 (n = 61) to equivalent (1:1) doses of either SARAsp-Mix or NN-Mix at least twice daily (1:1 randomization). In this subgroup analysis, efficacy measures [change in hemoglobin A1c (HbA1c), daily insulin dose], and safety outcomes [hypoglycemia incidence, adverse events (including hypersensitivity and injection site reactions), anti-insulin aspart antibodies] of SARAsp-Mix were compared with those of NN-Mix separately according to the participants' prestudy premix insulin. RESULTS: At week 26, change from baseline in HbA1c (primary efficacy endpoint) was similar between SARAsp-Mix and NN-Mix in those participants pretreated with NovoMix 30 [least squares (LS) mean difference 0.05%, 95% confidence interval (CI) -0.195% to 0.289%] or Humalog Mix 25/Liprolog Mix 25 (LS mean difference 0.28%, 95% CI -0.279% to 0.830%) (P value for treatment-by-subgroup interaction = 0.46). In both subgroups, safety outcomes, including immunogenicity, and changes in daily insulin doses were similar between treatments over 26 weeks. CONCLUSIONS: Efficacy, safety, and immunogenicity profiles of SARAsp-Mix are similar to NN-Mix over 26 weeks in adults with diabetes irrespective of prior type of premix insulin. TRIAL REGISTRATION: EudraCT number 2017-000092-84.

Role and importance of high fiber in diabetes management in India.

BACKGROUND & AIMS: India is facing a triple burden of pre-diabetes, diabetes, and obesity. Unhealthy eating habits and physical inactivity have been linked to the onset and progression of type 2 diabetes mellitus (T2DM). Despite dietary recommendations, individuals consume inadequate amounts or unsuitable type of dietary fiber (DF) which needs correction. An Expert group attempted to review and report on the role and importance of high DF in the management of T2DM and offer practical guidance on high fiber use in daily diet. METHODOLOGY: Twelve diabetologists and two expert dietitians from India were chosen to ensure diversity of the members both in professional interest and cultural background. The authors convened virtually for one group meeting and actively participated in a detailed discussion. Multiple reviews of the draft document followed by focused teleconference calls & email helped to reach consensus on final recommendations between Aug 2021 and Dec 2021. RESULTS: Evidence has shown that medical nutrition therapy (MNT) is a valuable approach and an essential component of T2DM prevention and management. Studies have shown that fiber rich diabetes nutrition (FDN) has multi-systemic health benefits, including, improvement in glycemic control, reduction in glucose spikes, decrease in hyperinsulinemia, improvement in plasma lipid concentrations and weight management in T2DM patients. CONCLUSION: A high fiber diet is vital for people with diabetes and associated conditions. Increasing fiber intake, preferably through food or through dietary supplement, may help. Fiber rich diabetes nutrition (FDN) is recommended in order to prevent and manage T2DM.

Biosimilar Insulin Aspart Premix SAR341402 Mix 70/30 Versus Originator Insulin Aspart Mix 70/30 (NovoMix 30) in People with Diabetes: A 26-Week, Randomized, Open-Label Trial (GEMELLI M).

INTRODUCTION: This study compared the efficacy, safety, and immunogenicity of biosimilar insulin aspart premix SAR341402 Mix 70/30 (SARAsp-Mix) with European-approved insulin aspart mix 70/30 - NovoMix® 30 (NN-Mix) in people with type 1 (T1D) or type 2 diabetes (T2D). METHODS: This 26-week, open-label, phase 3 trial enrolled 402 people with T1D (n = 105) or T2D (n = 297) previously treated with premix insulin, who were randomized (1:1) to SARAsp-Mix (n = 204) or NN-Mix (n = 198). RESULTS: After 26 weeks, the least squares (LS) mean [median] change in HbA1c from baseline was similar in both treatment groups (SARAsp-Mix - 0.55% [- 0.60%]; NN-Mix - 0.64% [- 0.60%]). The LS mean difference for SARAsp-Mix versus NN-Mix was 0.08%, with the upper bound of the two-sided 95% confidence interval (- 0.139 to 0.303) slightly above the prespecified noninferiority margin of 0.3%. Noninferiority of SARAsp-Mix over NN-Mix was not demonstrated in the primary intent-to-treat analysis, primarily because of one extreme outlying value impacted by the COVID-19 pandemic in the SARAsp-Mix group. Noninferiority was achieved in all secondary analyses, including prespecified per-protocol supportive and COVID-19 sensitivity analyses, as well as post hoc sensitivity analyses. Other efficacy endpoints, insulin dosages, anti-insulin aspart antibody response, hypoglycemia, and adverse events were similar between groups. CONCLUSIONS: The totality of evidence indicates that SARAsp-Mix provides effective glycemic control with a similar safety and immunogenicity profile to NN-Mix in people with diabetes treated for 26 weeks. TRIAL REGISTRATION: EudraCT number 2017-000092-84.

Real-World Observational Study of Glimepiride and Metformin Fixed-Dose Combination Along With Insulin in the Management of Type 2 Diabetes Mellitus: Indian Experience.

Background Type 2 diabetes mellitus (T2DM) is associated with a significant burden on both patients and the healthcare system. This study aimed to evaluate the demographics of patients with T2DM receiving different strengths of glimepiride and metformin combination along with insulin. This study also examined the concomitant conditions and therapies, duration of therapies, dosage titration, glycated hemoglobin (HbA1c) levels, hypoglycemic events, and weight changes during the course of therapy. Methods This retrospective, multicenter (347), observational study included adult patients with T2DM who received glimepiride and metformin combination along with insulin. Data related to demographic characteristics, duration of disease, co-morbidities, concomitant medications, and dosage pattern was collected from medical records authenticated by physicians during routine care. Results A total of 7058 patients were included in the study. The median age of included patients was 55 years and around 29% were aged >60 years and 60% were men. The majority of patients (83.3%) had insulin treatment initiation after glimepiride and metformin combination while other patients (16.7%) received glimepiride and metformin combination after insulin initiation. The mean HbA1c levels significantly decreased with a mean change of 1.33%. In one-third of the patients, down-titration of the insulin dose was done, indicating the insulin-sparing effect with the addition of the glimepiride and metformin combination. The most common comorbid condition was hypertension (64.7%). Of 3705 patients, 33.2% patients had weight loss and 66.8% had weight gain. A total of 432 patients reported hypoglycemic events. Physician global evaluation of efficacy and tolerability showed a good to excellent on the scale (97.3% and 96.6%). Conclusion This study presented good HbA1c lowering with glimepiride and metformin combination with insulin, ensuring a positive clinical outcome. Good to excellent efficacy and tolerability were observed in patients with T2DM across the age groups, in early as well as long-standing disease.

Blood glucose levels should be considered as a new vital sign indicative of prognosis during hospitalization.

BACKGROUND AND AIMS: The measurement of vital signs is an important part of clinical work up. Presently, measurement of blood glucose is a factor for concern mostly when treating individuals with diabetes. Significance of blood glucose measurement in prognosis of non-diabetic and hospitalized patients is not clear. METHODS: A systematic search of literature published in the Electronic databases, PubMed and Google Scholar was performed using following keywords; blood glucose, hospital admissions, critical illness, hospitalizations, cardiovascular disease (CVD), morbidity, and mortality. This literature search was largely restricted to non-diabetic individuals. RESULTS: Blood glucose level, even when in high normal range, or in slightly high range, is an important determinant of morbidity and mortality, especially in hospitalized patients. Further, even slight elevation of blood glucose may increase mortality in patients with COVID-19. Finally, blood glucose variability and hypoglycemia in critically ill individuals without diabetes causes excess in-hospital complications and mortality. CONCLUSION: In view of these data, we emphasize the significance of blood glucose measurement in all patients admitted to the hospital regardless of presence of diabetes. We propose that blood glucose be included as the "fifth vital sign" for any hospitalized patient.

Sustained release of curcumin from fibrin matrix induces cancer cell death and immunomodulation.

Despite the role of curcumin in controlling inflammation, angiogenesis, and cancer in human cells, its therapeutic use is limited. The reasons are quick metabolic breakdown, low aqueous solubility, and bioavailability. This study describes the advantages of clinical-grade curcumin-incorporated fibrin matrix either in lyophilized off-the-shelf wafer or injectable hydrogel forms, as a biodegradable local delivery system. To produce the curcumin-fibrin wafer, used clinical-grade fibrin sealant in a modified composition. To fabricate wafer, we premixed the curcumin with either fibrinogen or thrombin, before clotting into a hydrogel. Sustained release of active curcumin from fibrin wafer, suspended in culture medium at 37 °C lasted for seven days. Upon premixing albumin with thrombin and subsequently adding curcumin into the mixture improved the loading concentration and stability. Dose- and time-dependent apoptotic function of curcumin on cancer cell lines upon release from fibrin wafer, were demonstrated in vitro. In vivo immuno-modulation and a nontoxic response to curcumin released from fibrin into the peritoneal cavity of mice were established. The cytotoxic effect of released curcumin was demonstrated; showing both a preventive and therapeutic role against tumor growth. In vivo studies used Dalton's Lymphoma Ascites (DLA) mice model. Both implanted fibrin wafer and injected hydrogel can breakdown by a physiological process and get cleared by the fibrinolytic mechanism. The lyophilized fibrin wafer could function as a hemostat, adhere to surgical cancer tissues, and arrest bleeding. The potential of curcumin in preventing solid tumor metastasis may be explored upon the sustained delivery of the molecule from the fibrin wafer.

Remogliflozin Etabonate in the Treatment of Type 2 Diabetes: Design, Development, and Place in Therapy.

Type 2 diabetes mellitus (T2DM) is an emerging epidemic in Asian countries, especially in India. With the advent of the SGLT2 inhibitor class of drugs demonstrating benefits beyond glycemic control, viz. weight loss, blood pressure reduction, and cardiovascular and renal protection, the management of T2DM has taken a quantum leap. Remogliflozin etabonate (RE) is the latest addition to the SGLT2 inhibitor class of drugs that have been recently approved in India for the management of T2DM. RE is a potent and selective inhibitor of SGLT2 with the unique distinction of being administered as a prodrug, existence of active metabolites, and short half-life necessitating twice-daily dosing. The Phase III study of RE demonstrated it to be an efficacious and safe agent and non-inferior to the currently available SGLT2 inhibitors. This paper reviews not only the pharmacokinetics, pharmacodynamics, clinical efficacy, and safety profile of RE but also its molecular and clinical development program. This review has taken into consideration all available published as well as unpublished literature on RE and discusses the individual studies performed during its development for characterization of pharmacological profile.

Efficacy and Safety of Remogliflozin Etabonate, a New Sodium Glucose Co-Transporter-2 Inhibitor, in Patients with Type 2 Diabetes Mellitus: A 24-Week, Randomized, Double-Blind, Active-Controlled Trial.

BACKGROUND: Metformin is the first-line treatment for type 2 diabetes mellitus (T2DM), but many patients either cannot tolerate it or cannot achieve glycemic control with metformin alone, so treatment with other glucose-lowering agents in combination with metformin is frequently required. Remogliflozin etabonate, a novel agent, is an orally bioavailable prodrug of remogliflozin, which is a potent and selective sodium-glucose co-transporter-2 inhibitor. OBJECTIVE: Our objective was to evaluate the efficacy and safety of remogliflozin etabonate compared with dapagliflozin in subjects with T2DM in whom a stable dose of metformin as monotherapy was providing inadequate glycemic control. METHODS: A 24-week randomized, double-blind, double-dummy, active-controlled, three-arm, parallel-group, multicenter, phase III study was conducted in India. Patients aged ≥ 18 and ≤ 65 years diagnosed with T2DM, receiving metformin ≥ 1500 mg/day, and with glycated hemoglobin (HbA1c) levels ≥ 7 to ≤ 10% at screening were randomized into three groups. Every patient received metformin ≥ 1500 mg and either remogliflozin etabonate 100 mg twice daily (BID) (group 1, n = 225) or remogliflozin etabonate 250 mg BID (group 2, n = 241) or dapagliflozin 10 mg once daily (QD) in the morning and placebo QD in the evening (group 3, n = 146). The patients were followed-up at weeks 1 and 4 and at 4-week intervals thereafter until week 24. The endpoints included mean change in HbA1c (primary endpoint, noninferiority margin = 0.35), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), bodyweight, blood pressure, and fasting lipids. Treatment-emergent adverse events (TEAEs), safety laboratory values, electrocardiogram, and vital signs were evaluated. RESULTS: Of 612 randomized patients, 167 (group 1), 175 (group 2), and 103 (group 3) patients with comparable baseline characteristics completed the study. Mean change ± standard error (SE) in HbA1c from baseline to week 24 was - 0.72 ± 0.09, - 0.77 ± 0.09, and - 0.58 ± 0.12% in groups 1, 2, and 3, respectively. The difference in mean HbA1c of group 1 versus group 3 (- 0.14%, 90% confidence interval [CI] - 0.38 to 0.10) and group 2 versus group 3 (- 0.19%; 90% CI - 0.42 to 0.05) was noninferior to that in group 3 (p < 0.001). No significant difference was found between group 1 or group 2 and group 3 in change in FPG, PPG, and bodyweight. The overall incidence of TEAEs was comparable across study groups (group 1 = 32.6%, group 2 = 34.4%, group 3 = 29.5%), including adverse events (AEs) of special interest (hypoglycemic events, urinary tract infection, genital fungal infection). Most TEAEs were mild to moderate in intensity, and no severe AEs were reported. CONCLUSION: This study demonstrated the noninferiority of remogliflozin etabonate 100 and 250 mg compared with dapagliflozin, from the first analysis of an initial 612 patients. Remogliflozin etabonate therefore may be considered an effective and well-tolerated alternative treatment option for glycemic control in T2DM. TRIAL REGISTRATION: CTRI/2017/07/009121.

Consensus Statement on Use of Ambulatory Glucose Profile in Patients with Type 2 Diabetes Mellitus Receiving Oral Antidiabetic Drugs.

Glucose monitoring is an important aspect of diabetes care. The traditional methodologies of blood glucose monitoring such as fasting plasma glucose, post prandial glucose, glycosylated hemoglobin and self-monitoring of blood glucose do not adequately address hypoglycemia and glycemic variability, which are two important risk factors for diabetes-related complications. Ambulatory glucose profile (AGP) developed from a continuous glucose monitoring system is a simplified report, with standardized statistics and targets and visual representation of time in standardized glycemic ranges, glucose variability, and glycemic exposure over a single 24-h day. The role of AGP in T2DM patients who are on oral anti-diabetic drugs (OADs) is still not clearly defined. An expert group of endocrinologists and diabetologists met in Pune, India to discuss the role of AGP in T2DM patients on OADs. This article aims to discuss the consensus of the expert group on the role of AGP in T2DM patients on OADs and also reviews the various aspects of AGP and its interpretation; and the available evidences for disease management including treatment options based on AGP report.

Strengthening the Family - the 'Five-I' Approach.

This article describes the importance of the family in diabetes care. It lists the multiple ways in which the family is related to diabetes: as a cause or culprit of diabetes, as a tool or technique for delivering diabetes care and as a target of diabetes or diabetes-care-related complications. The authors suggest an alliterative 'Five-I' approach to guide diabetes care professionals in addressing needs, and utilising strengths, of the family of a person with diabetes. The five 'I's stand for: involved independence, iterative information, interactive interviews, inspired introspection and integrated incorporation. This strategy, based upon evidence and experience, is supported by pragmatism and practicality.

Immunostimulatory plant polysaccharides impede cancer progression and metastasis by avoiding off-target effects.

An unexploited homo-polysaccharide (PSM001) isolated from the seed kernel of Kottukonam variety of Mangifera indica, demonstrated selective cytotoxicity against cancer cells both in vitro and in murine models while maintaining the immunostimulatory potential. Galactoxyloglucan (PST001) isolated from the seeds of Tamarindus indica, was previously established to be an effective anticancer and immunomodulatory agent. Cancer metastasis, with key features including invasion, migration, increased angiogenesis and colony formation is only likely to accentuate in the coming decades, considering the ground realities of the modern lifestyle and environmental factors and hence both the polysaccharides were tested towards the management of malignancy. It was a startling observation with both the biopolymers in inhibiting various processes involved in the metastatic cascade. A quick perusal of the issue at hand would throw up the promising ability of both PSM001 and PST001 to inhibit lung metastatic nodules of C57BL/6 mice wherein the combinatorial treatment of these polysaccharides with vincristine delivered superior therapeutic output. Later, vascular endothelial growth factor and multiple matrix metalloproteinases were found to be the lead players in the polysaccharide mediated metastatic inhibition. Having considered the complexities associated with the chemotherapy in metastatic cancer in terms of palpable immunosuppression, the aftermaths with the co-administration of an immunostimulatory agent which itself possess unique anticancer and anti-metastatic potentials with a potent chemotherapeutic agent will be enormously consequential.

Recommendations for in-clinic PoCT for diabetes management in India.

A panel of expert diabetologist clinicians developed consensus standards to address the quality gaps inclinic point of care testing (PoCT) especially pertaining to diabetes care and management in India. The following summarized principles were established- 1. PoCT definition, 2. Advantages and critical aspects of PoCT including guideline recommendations and accreditations, analytical factors (pre &post analytical included) and consensus reached for an ideal PoC analyzer and 3. Key recommendations on in-clinic PoCT implementation by the panel. The experts suggested next steps that included key comparative (PoCT vs NGSP accredited lab) and patient benefit studies on PoCT.

The role of p53-microRNA 200-Moesin axis in invasion and drug resistance of breast cancer cells.

This study aimed to analyze the expression of microRNAs in relation to p53 status in breast cancer cells and to delineate the role of Moesin in this axis. We used three isogenic breast carcinoma cell lines MCF7 (with wild-type p53), 1001 (MCF7 with mutated p53), and MCF7-E6 (MCF7 in which p53 function was disrupted). MicroRNA expression was analyzed using microarray analysis and confirmed by real-time polymerase chain reaction. The 1001 clone with mutant p53 showed 22 upregulated and 25 downregulated microRNAs. The predicted targets of these 47 microRNAs were >700 human genes belonging to interesting functional groups such as stem cell development and maintenance. The most significantly downregulated microRNAs in the p53-mutant cell line were from the miR-200 family. We focused on miR-200c which targets many transcripts involved in epithelial-to-mesenchymal transition including Moesin. We found that Moesin was expressed in 1001 but not in its p53 wild-type parental MCF7 consistent with the observed mesenchymal features in the 1001, such as vimentin positivity, E-cadherin negativity, and ZEB1 positivity in addition to the morphological changes. After Moesin silencing, the p53-mutant cells 1001 reverted from mesenchymal-to-epithelial phenotype and showed subtle reduction in migration and invasion and loss of ZEB1 and SNAIL expression. Interestingly, Moesin silencing restored the 1001 sensitivity to Doxorubicin. These results indicate that loss of miR-200c, as a consequence of p53 mutation, can upregulate Moesin oncogene and thus promote carcinogenesis. Moesin may play a role in metastasis and drug resistance of breast cancer.

Role of AXL in invasion and drug resistance of colon and breast cancer cells and its association with p53 alterations.

AIM: To characterize AXL receptor tyrosine kinase (AXL) expression in relationship to tumor protein P53 (TP53 gene, p53 protein) and its role in tumor invasion and response to therapy. METHODS: We used 14 cell lines, including 3 isogenic pairs carrying mutant/knockout p53, to gain insight into the relationship between AXL and TP53. These included HCT116, HCT116.p53 mutant, RKO, and RKO.p53-/- lines (all from colon cancers) as well as breast cancer cell lines MCF7 and 1001 (MCF7-p53 mutant clone). HeLa cell line was used as a positive control for epithelial to mesenchymal transition (EMT). AXL expression was determined by Western blotting using rabbit monoclonal antibody clone C89E7. AXL siRNA silencing was performed and followed by collagen invasion assay. Cell viability analysis using the sulforhodamine B assay and the invasion assay were performed after exposure to chemotherapeutic agents (doxorubicin for breast cancer cells; 5FU or irinotecan for colon cancer cells). RESULTS: We showed that the introduction of p53 mutations or knockout increased expression levels of AXL in isogenic cells compared to the matching p53 wild-type parental cells. Overall, we found a trend for correlation between the potential EMT candidate AXL, p53 alterations, and EMT markers in colorectal and breast cancers. The expression of AXL in RKO cells, a rare colon cancer cell line with inactive Wnt signaling, suggests that the AXL oncogene might provide an alternative genetic pathway for colorectal carcinogenesis in the absence of Wnt signaling activation and TP53 mutation. AXL silencing in the TP53 mutant isogenic cell lines 1001, HCT116.p53 mutant and RKO.P53-/- was > 95% efficient and the silenced cells were less invasive compared to the parental TP53 wild-type cells. AXL silencing showed a subtle trend to restore colon cancer cell sensitivity to 5FU or irinotecan. Importantly, AXL expressing cells developed more invasive potential after exposure to chemotherapy compared to the AXL-silenced cells. CONCLUSION: AXL is influenced by p53 status and could cause the emergence of aggressive clones after exposure to chemotherapy. These findings could have applications in cancer management.