Core Pathways
|
| RAS |
KRAS, MAP2K4 |
Combined MEK/PI3K inhibition, target KRAS directly or indirect (i.e., metabolic pathways) |
[23, 75] |
| G1/S checkpoint |
CDKN2A/B, TP53, RB |
CDK4/6 inhibition, but may require further inhibition of MTOR, MEK or other pathways |
[51] |
| TGFβ signaling |
SMAD4, TGFBR1, ACVR1B |
SMAD4 loss is a marker of poor prognosis |
[76] |
| Wnt signaling |
RNF43, AXIN1/2, GATA6 |
Porcupine, tankyrase and FZD inhibitors, other direct and indirect inhibitors of Wnt |
[53, 56] |
| NOTCH |
JAG2, NOTCH1-4, MAML1 |
Gamma-secretase/NOTCH inhibitors in trials |
[43] |
| Hedgehog signaling |
SMO, GLI1-3, LRP2 |
Stromal targeting; SMO and GLI inhibitors |
[18, 70] |
| Integrin |
ITGA4, ITGA9, ILK, LAMA1/4/5 |
Mediate tumor-stromal interactions, possible targets for stromal therapy |
[77] |
| Small GTPase signaling |
ARHGEF9, RP1, CDC42BPA |
Important downstream effector pathway for KRAS that may warrant targeting |
[20] |
| JNK signaling |
MAP4K3, TNF, ATF2 |
JNK inhibitors may inhibit PDA stem cells |
[78] |
| DNA damage response |
BRCA1/2, PALB2, ATM |
Potential response to platinum agents, mitomycin C or PARP inhibitors |
[41] |
| Invasion |
ADAM11-12, PRSS23 |
Cancer hallmark, general or specific inhibitors |
[79] |
| Homophilic cell adhesion |
CDH1-2, FAT, PCDH15 |
EMT, invasion and metastasis |
[79] |
| Apoptosis |
CASP10, CAD, HIP1 |
Cancer hallmark, general or specific inhibitors |
[79] |
| Chromatin regulation |
ARID1A/1B, PRBM1, KDM6A, SETD1A, MLL1-4 |
ARID1A is prognostic; histone modifying agents, susceptibility to EZH2 inhibitor? |
[42, 43] |
| Axon guidance |
ROBO1/2, SLIT2, EPHA5/7, SEMA3A/3E/5A |
Markers of poor prognosis, activate MET and WNT signaling (could alter drug response) |
[44] |
|
Additional Pathways or Actionable Targets
|
| RNA processing |
RBM10, SF3B1, U2AF1 |
RBM10 linked to prognosis based on KRAS alteration |
[42] |
| HIPPO/FAT |
FAT1-4, DCHS1-2, LATS1 |
Potential resistance to KRAS inhibitor; direct/indirect inhibitors of YAP/TEAD? |
[31, 33] |
| Mismatch repair |
MLH1, MSH2 |
Increased PDA risk with Lynch syndrome; marker of chemotherapy or anti-PD1 response? |
[80] |
| MYC |
MYC amplification |
Worse prognosis/adenosquamous histology; use of CDK9 or BET inhibitors |
[42, 43] |
| KRAS wild-type |
PIK3CA, BRAF, STK11, GNAS, CHEK2 |
Alternative oncogenic drivers; possible response to BRAF or EGFR inhibitors? |
[42] |
