KIT ATP-Binding Pocket/Activation Loop Mutations in GI Stromal Tumor: Emerging Mechanisms of Kinase Inhibitor Escape.

PURPOSE: Imatinib resistance in GI stromal tumors (GISTs) is primarily caused by secondary KIT mutations, and clonal heterogeneity of these secondary mutations represents a major treatment obstacle. KIT inhibitors used after imatinib have clinical activity, albeit with limited benefit. Ripretinib is a potent inhibitor of secondary KIT mutations in the activation loop (AL). However, clinical benefit in fourth line remains limited and the molecular mechanisms of ripretinib resistance are largely unknown. PATIENTS AND METHODS: Progressing lesions of 25 patients with GISTs refractory to ripretinib were sequenced for KIT resistance mutations. Resistant genotypes were validated and characterized using novel cell line models and in silico modeling. RESULTS: GISTs progressing on ripretinib were enriched for secondary mutations in the ATP-binding pocket (AP), which frequently occur in cis with preexisting AL mutations, resulting in highly resistant AP/AL genotypes. AP/AL mutations were rarely observed in a cohort of progressing GIST samples from the preripretinib era but represented 50% of secondary KIT mutations in patients with tumors resistant to ripretinib. In GIST cell lines harboring secondary KIT AL mutations, the sole genomic escape mechanisms during ripretinib drug selection were AP/AL mutations. Ripretinib and sunitinib synergize against mixed clones with secondary AP or AL mutants but do not suppress clones with AP/AL genotypes. CONCLUSION: Our findings underscore that KIT remains the central oncogenic driver even in late lines of GIST therapy. KIT-inhibitor combinations may suppress resistance because of secondary KIT mutations. However, the emergence of KIT AP/AL mutations after ripretinib treatment calls for new strategies in the development of next-generation KIT inhibitors.

Addressing the Osimertinib Resistance Mutation EGFR-L858R/C797S with Reversible Aminopyrimidines.

Drug resistance mutations emerging during the treatment of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) inhibitors represent a major challenge in personalized cancer treatment and require constant development of new inhibitors. For the covalent irreversible EGFR inhibitor osimertinib, the predominant resistance mechanism is the acquired C797S mutation, which abolishes the covalent anchor point and thus results in a dramatic loss in potency. In this study, we present next-generation reversible EGFR inhibitors with the potential to overcome this EGFR-C797S resistance mutation. For this, we combined the reversible methylindole-aminopyrimidine scaffold known from osimertinib with the affinity driving isopropyl ester of mobocertinib. By occupying the hydrophobic back pocket, we were able to generate reversible inhibitors with subnanomolar activity against EGFR-L858R/C797S and EGFR-L858R/T790M/C797S with cellular activity on EGFR-L858R/C797S dependent Ba/F3 cells. Additionally, we were able to resolve cocrystal structures of these reversible aminopyrimidines, which will guide further inhibitor design toward C797S-mutated EGFR.

Long-term mucosal recovery and healing in celiac disease is the rule - not the exception.

OBJECTIVE: The prevalence of persistent villous atrophy (VA) in patients with celiac disease (CD) on a gluten-free diet (GFD) varies greatly between studies. Most studies show a relatively high prevalence of mucosal atrophy and inflammation in treated patients, a finding which have led to a concept of non-responsive CD. Few studies have examined the prevalence of long-term mucosal healing. Our study aimed to determine the extent of mucosal healing in a cohort of Norwegian patients with CD treated with GFD for several years. MATERIALS AND METHODS: Adult patients diagnosed with VA between 1989 and 2009 were included. We performed a follow-up gastroscopy with duodenal biopsies. Two pathologists evaluated the biopsies according to the Marsh-Oberhuber classification. Mucosal healing was defined as Marsh 0 while mucosal recovery was defined as Marsh 0-2. RESULTS: Duodenal biopsies were obtained from 127 adult patients with established CD. After a follow-up time of 8.1 years (median, range 2.3-22.3), 103 (81%) of the patients showed mucosal healing, 120 patients (94%) showed mucosal recovery, and 7 patients (6%) showed persistent VA. In addition, 103 of the 127 patients (81%) had undergone a routine follow-up biopsy 12.6 months (median, range 5.2-28.8) after diagnosis. At the time of the routine follow-up, only 52 of these patients (50.5%) had achieved mucosal recovery. CONCLUSIONS: Although half of the patients had persistent VA at the time of routine follow-up, both long-term mucosal recovery and healing is possible for the vast majority of adult patients with CD.

Clinical course in Crohn's disease: results of a five-year population-based follow-up study (the IBSEN study).

BACKGROUND: There are few population-based, prospective studies on the clinical course in patients with Crohn's disease (CD). AIM: To extend the observation period in a population-based prospective study (the IBSEN study) to find out more about the initial 5-year clinical course in CD patients and to relate the findings to the Vienna classification. METHODS: All patients diagnosed with inflammatory bowel disease (IBD) in southeastern Norway in the 4 years 1990-1993 were followed prospectively. The patients were invited to a systematic follow-up visit at their local hospital 1 and 5 years after inclusion in the study. The visits included a structured interview, a clinical examination and colonoscopy. RESULTS: Out of 843 patients initially diagnosed with IBD, 200 patients with definite CD were alive and had sufficient data for analysis 5 years after diagnosis. Changes in disease localization and behaviour in relation to the Vienna classification were observed in 27 (13.5%) and 35 patients (17.5%), respectively. During the observation period, 56 patients (28%) underwent surgery with intestinal resection, and half of these had disease localized in the terminal ileum. At the time of the 5-year visit, oral sulfasalazin and 5-aminosalicylic acid (5-ASA) were the most frequently used medications (by 54% of the patients), while oral glucocorticosteroids and azathioprine were being used by 25% and 13%, respectively. Seventy-two percent of the patients had taken oral glucocorticosteroids at some time in the course of the 5-year period. The majority of the patients had intestinal symptoms at 5 years, but only 16% had symptoms that interfered with everyday activities. Fourteen percent of the patients had had a relapse-free 5-year course; however, relapse was not related to the initial Vienna classification. When the patients described the clinical course, 44% reported an improvement in symptoms during the follow-up period. CONCLUSIONS: The 5-year clinical course in an unselected cohort of CD patients was mostly mild. The frequency of surgery was lower than that observed in other studies and only a minority of the patients had symptoms that interfered with everyday activities 5 years after the initial diagnosis. The Vienna classification predicted the risk of surgery, but did not predict symptoms at 5 years, relapses during the observation period or the course of disease as described by the patients.

Change of diagnosis during the first five years after onset of inflammatory bowel disease: results of a prospective follow-up study (the IBSEN Study).

OBJECTIVE: An exact diagnosis of inflammatory bowel disease (IBD) and further subclassification may be difficult even after clinical, radiological and histological examinations. A correct subclassification is important for the success of both medical and surgical therapeutic strategies, but there is a dearth of information available on the frequency of changes in diagnosis in population-based studies. The objective of this work was prospectively to re-evaluate the diagnosis in an unselected cohort of IBD patients during the first five years after the initial diagnosis. MATERIAL AND METHODS: Patients classified as IBD or possible IBD in the period 1990-94 (the IBSEN cohort) had their diagnosis re-evaluated after 1 and 5 years. Initially, the patients were classified as ulcerative colitis (UC), Crohn's disease (CD), indeterminate colitis (IC) or possible IBD. At the 5-year visit, patients were classified as UC, CD or non-IBD. RESULTS: A total of 843 patients (518 UC, 221 CD, 40 IC and 64 possible IBD) were identified. Clinical information was available for 94% of the patients who survived after 5 years. A change in diagnosis was found in 9% of the patients initially classified as UC or CD. A change to non-IBD was more frequent than a change between UC and CD. A large proportion of patients initially classified as IC or possible IBD were diagnosed as non-IBD after 5 years (22.5% versus 50%). When IBD was confirmed in these groups, UC was more frequent than CD. Two changes in diagnosis during follow-up were observed in 2.8% of the patients; this was more frequent in patients initially classified as IC or possible IBD. CONCLUSIONS: There are obvious diagnostic problems in a minority of patients with IBD; a systematic follow-up is therefore important in these patients.

Ulcerative colitis and clinical course: results of a 5-year population-based follow-up study (the IBSEN study).

BACKGROUND: The majority of studies concerning the clinical course and prognosis in ulcerative colitis (UC) are old, retrospective in design, or hospital based. We aimed to identify clinical course and prognosis in a prospective, population-based follow-up study MATERIALS AND METHODS: Patients diagnosed with inflammatory bowel disease (IBD) or possible IBD in southeastern Norway during the period 1990-1994 were followed prospectively for 5 years. The evaluation at 5 years included an interview, clinical examination, laboratory tests, and colonoscopy. RESULTS: Of 843 patients diagnosed with IBD, 454 patients who had definite UC and for whom there were sufficient data for analysis were alive 5 years after inclusion in the study. The frequency of colectomy in this population was 7.5%. Forty-one percent of the patients were not taking any kind of medication for IBD at 5 years. Of the patients initially diagnosed with proctitis, 28% had progressed during the observation period, 10% to extensive colitis. The majority of the patients (57%) had no intestinal symptoms at 5 years, and only a minority (7%) had symptoms that interfered with everyday activities. Among the patients who underwent colonoscopy at the 5-year visit, symptoms were frequently reported in patients without macroscopic inflammation (44%). A relapse-free course was observed in 22% of the patients. A decrease in symptoms during the follow-up period was the most frequent course taken by the disease and was observed in 59% of the cases. The extent of disease was unrelated to symptoms at 5 years and also to relapse rate and course of disease during the 5-year period. CONCLUSIONS: The disease course and prognosis of UC appears better than previously described in the literature. The frequency of surgery was low, and only a minority of the patients had symptoms that interfered with their everyday activities 5 years after diagnosis.

Course of disease, drug treatment and health-related quality of life in patients with inflammatory bowel disease 5 years after initial diagnosis.

OBJECTIVES: We assessed health-related quality of life (HRQOL) on the basis of a cross-sectional design in a population-based cohort of inflammatory bowel disease patients followed prospectively for 5 years after diagnosis. The aim was to investigate the influence of the course of disease, drug therapy, and relapse pattern on the patients' HRQOL. METHODS: All patients completed the validated Norwegian version of the Inflammatory Bowel Disease Questionnaire (N-IBDQ). We present data from 497 patients, 328 with ulcerative colitis and 169 with Crohn's disease. The mean age was 43.3 years, and 48% were female. RESULTS: Crohn's disease patients treated with systemic steroids or azathioprine had a statistically significant reduction in the N-IBDQ total score compared with non-users. Patients with a more severe disease pattern had a lower N-IBDQ total score. Patients reporting a relapse during the observation period had a significantly lower total score and dimension scores than patients without relapse in both diagnostic groups, and likewise there was a statistically significant decrease in N-IBDQ total score for those with extra-intestinal manifestations compared with those without. A multiple linear regression model showed that the number of relapses during the preceding year in ulcerative colitis, and sex (female gender) in Crohn's disease were the strongest predictor of a reduction in N-IBDQ total score. CONCLUSION: Treatment with systemic steroids or immunosuppressive drugs, a relapsing disease and the presence of extra-intestinal manifestations were associated with a clinically significant reduction in the patients' HRQOL.