Abstract 34P
Background
RAS mutated colon cancer has a worse prognosis than wild type (wt) with a median of about 20 months of OS and the BRAF mutated with an OS of about 10 months. In addition, we frequently find patients with therapeutic exhaustion. The objective of the present study is the definition of molecular markers of response to traditional chemotherapeutic agents and new drugs studied in RAS / BRAF mutated colon cancer.
Methods
The following colon cancer cell lines were used: HCT15, T84, HT29 and SW480 (molecular characteristics are summarized in the table). These cell lines were assigned to 5-fluorouracil, oxaliplatin, irinotecan, gemcitabine, pemetrexed, trabectidine and eribulin at different doses for 72 hours in order to obtain the inhibitory concentration 50 values (IC50). Likewise, RT-PCR studies were carried out in order to determine the expression of P-glycoprotein.
Results
The results of IC50 (μM) obtained in the colon cancer cell lines for the different drugs are summarized in the table. The results of the RT-PCR revealed the presence of P-Glycoprotein in HCT15 and the absence of expression of this protein in the rest of the cell lines studied. The sensitivity to 5-FU and GMZ in the studies seems to correspond to the wt forms of p53 and SMAD4, this last closely related to p21. OXA sensitivity is related to the mutated forms of p53 and SMAD4. IRI is related to the degree of tumor cell differentiation, the most undifferentiated being more sensitive (CMS 1 and 4). IRI, PEM and TRABECT sensitivity is linked to the wt form of APC. In the case of ERIB, the most resistant line is the one that expresses P-glycoprotein. Table: 34P
| T84 | HCT15 | SW480 | HT29 | |
| 5-FU IC50 (μM) | 2,76 | 6,23 | 6,57 | 8,6 |
| OXAIC50 (μM) | 6,06 | 2,47 | 2,44 | 1,77 |
| IRI IC50 (μM) | 18,24 | 9,61 | 4,24 | 22,15 |
| GMZ IC50 (μM) | 0,21 | 0,3 | 0,4 | 0,61 |
| PEM IC50 (μM) | 0,24 | 0,21 | 0,06 | 0,31 |
| ERIB IC50 (μM) | 0,00097 | > 0,0075 | 0,00010 | 0,00090 |
| TRABEC IC50 (μM) | 0,00140 | 0,00170 | 0,00045 | 0,00200 |
| RAS/BRAF | RAS mut | RAS mut | RAS mut | BRAF mut |
| p53 | wt | mut | mut | mut |
| Microsatelite | MSS | MSI | MSS | MSS |
| PI3K | mut | mut | mut | mut |
| APC | mut | mut | wt | mut |
| SMAD4 | wt | wt | wt | mut |
| CMS | 2 (differentiated) | 1 (undifferentiated) | 4 (undifferentiated) | 3 (differentiated) |
Conclusions
1. The sensitivity to fluoropyrimidines is not related to the instability of microsatellites in the cell lines studied. 2. Sensitivity to different drugs correlates with different molecular markers in each case. 3. These results could help to choose the most appropriate treatments in advanced colon cancer and even when the basic therapeutic lines have been exhausted.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
SAS.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.