Strong synergy with APR-246 and DNA-damaging drugs in primary cancer cells from patients with TP53 mutant High-Grade Serous ovarian cancer

Fransson, Åsa; Glaessgen, Daria; Alfredsson, Jessica; Wiman, Klas G.; Bajalica-Lagercrantz, Svetlana; Mohell, Nina

doi:10.1186/s13048-016-0239-6

Table 1 Summary of results with APR-246 and cisplatin in primary cancer cells from the patients

From: Strong synergy with APR-246 and DNA-damaging drugs in primary cancer cells from patients with TP53 mutant High-Grade Serous ovarian cancer

Ascites sample	Diagnosis	Histological description	Prior chemo-therapy	Platinum sensitivity	IC₅₀ APR-246 (μM)	IC₅₀ cisplatin (μM)	p53 status	p53 protein levels	Combination APR-246 cisplatin
1	Ovarian cancer stage III	Poorly differentiated serous carcinoma^a	Yes	Resistant	25	40^*	R280K (hom.)	++	SS
2	Cancer peritonei stage IV	Serous carcinoma	Yes	Resistant	24	18	wt	−	S, Add
3	Ovarian cancer stage IC	Serous carcinoma	Yes	Resistant	37	32	L111Q (het.)	+	S, SS
4	Ovarian cancer/Cancer peritonei stage IV	Poorly differentiated serous carcinoma^a	Yes	Resistant	18	3.2	P151H (het.)	+	SS
5	Cancer peritonei stage IIIC	Serous adenocarcinoma, grade III^a	No	Sensitive	22	16	C135Y (hom.)	+	SS
6	Tubar cancer stage IIIB	Poorly differentiated serous adenocarcinoma^a	Yes	Sensitive	12	17	C238F (het.)	++	SS
7	Ovarian cancer stage IIIC	Poorly differentiated serous carcinoma^a	Yes	Resistant	56^d	45^d	E346^* (het.)	−	S, Add
8	Cancer Peritonei stage IV	Poorly differentiated serous carcinoma^a	No	Sensitive	8.9	7.1	E204^* (hom.)	−	SS
9	Ovarian cancer stage IIIC	Poorly differentiated serous carcinoma^a	Yes	Resistant	5.2	7.9	P278R (hom.)	+	SS
10	Ovarian cancer stage IIIC	Medium-well differentiated serous adenocarcinoma^a,b	Yes	Sensitive	8.0	17	Y163H (het.)	+	SS

Cell viability was assessed by the FMCA assay. Combination Index (CI) was calculated using the Additive model.
Diagnosis: The 10 samples included in the study were from patients diagnosed with ovarian, peritoneal, or fallopian tube cancer. Strong data suggest that high-grade serous (HGS) carcinomas found in these tissues share a similar origin and pathogenesis pointing out the distal part of the fallopian tubes as the origin in the majority of cases [2, 3].
Histological description: The primary histopathological analysis of the samples in this study was performed using the previous grading system and heterogeneous criteria and not according to the present standard where tumors are classified into low- and high-grade serous carcinomas.
^aThese samples are classified as HGS carcinoma according to the current criteria [16]. Likely is also sample 3 with TP53 mutation HGS carcinoma.
^bPatient 10 was later reoperated for distant metastasis and the histopathological analysis showed HGS tumor.
Platinum sensitivity: patients who relapse > 6 months are classified as platinum-sensitive; patient who relapse < 6 months are platinum-resistant.
p53 status: het. = heterozygous; hom. = homozygous; ^* = stop codon. The sequencing method used cannot distinguish homozygous from hemizygous mutations, neither can heterozygosity be distinguished from a mixture of cells with wild type and mutant TP53.
p53 protein levels:− = not detected; + = medium; ++ = high.
Combination APR-246 cisplatin: Add = additive effect (CI = 1.0 ± 0.2); S = synergy (CI < 0.8); SS = strong synergy (CI < 0.5).
^cThe dose-response curve of cisplatin levelled off and thus resulted in difficulty to determine the IC₅₀ value.
^dCisplatin and APR-246 had high IC₅₀ values in sample 7. Moreover, results from combination experiments in this sample were variable resulting in high standard error.

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ISSN: 1757-2215

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