Targeted Pathway Inhibition in Patients With Pancreatic Cancer

Inclusion Criteria: * Ability to understand and the willingness to sign a written informed consent document * Age \>= 18 years * Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 * Clinically-confirmed diagnosis of resectable, borderline resectable, locally-advanced or metastatic adenocarcinoma of the pancreas. * Patients with disease that is eligible for curative surgery may not be eligible for all study arms. * Participants may be treatment naïve or have received prior therapy for the treatment of their pancreatic ductal adenocarcinoma (PDAC). A minimum washout period of 10-days after completing the most recent line of therapy is required before a participant can initiate treatment with study agent(s) * Based on available imaging, participant must have at least one disease lesion that can be biopsied in accordance with institutional standards * Hemoglobin \>= 9.0 g/dL with no blood transfusion within 28 days of starting treatment (within 4 weeks prior to initiating window treatment). Note: laboratory tests performed after initial screening (but still within the screening window) will be evaluated by the investigator; should any of these values fall outside eligibility parameters, the patient may still be eligible per investigator discretion * White blood cells (WBC) \> 3 x 10\^9/L (within 4 weeks prior to initiating window treatment). Note: laboratory tests performed after initial screening (but still within the screening window) will be evaluated by the investigator; should any of these values fall outside eligibility parameters, the patient may still be eligible per investigator discretion * Absolute neutrophil count (ANC) \>= 1.5 x 10\^9/L (\> 1500 per mm\^3) (within 4 weeks prior to initiating window treatment). Note: laboratory tests performed after initial screening (but still within the screening window) will be evaluated by the investigator; should any of these values fall outside eligibility parameters, the patient may still be eligible per investigator discretion. * May be waived on a case-by-case basis for patient populations recognized to have normal baseline values below this level * Platelet count \>= 100 x 10\^9/L (\> 100,000 per mm\^3) (within 4 weeks prior to initiating window treatment). Note: laboratory tests performed after initial screening (but still within the screening window) will be evaluated by the investigator; should any of these values fall outside eligibility parameters, the patient may still be eligible per investigator discretion * Creatinine =\< 1.5 x upper limit of normal (ULN), OR measured or calculated creatinine clearance (glomerular filtration rate \[GFR\] can also be used in place of creatinine or creatinine clearance \[CrCl\]) \>= 60 mL/min/1.73m\^2 for participants with creatinine levels \> 1.5 x institutional ULN (within 4 weeks prior to initiating window treatment). Note: laboratory tests performed after initial screening (but still within the screening window) will be evaluated by the investigator; should any of these values fall outside eligibility parameters, the patient may still be eligible per investigator discretion. * Creatinine clearance should be calculated per institutional standard. For participants with a baseline calculated creatinine clearance below normal institutional laboratory values, a measured baseline creatinine clearance should be determined. Individuals with higher values felt to be consistent with inborn errors of metabolism will be considered on a case-by-case basis * Serum bilirubin =\< 1.5 x institutional upper limit of normal (ULN) (within 4 weeks prior to initiating window treatment). Note: laboratory tests performed after initial screening (but still within the screening window) will be evaluated by the investigator; should any of these values fall outside eligibility parameters, the patient may still be eligible per investigator discretion * Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x ULN (within 4 weeks prior to initiating window treatment). Note: laboratory tests performed after initial screening (but still within the screening window) will be evaluated by the investigator; should any of these values fall outside eligibility parameters, the patient may still be eligible per investigator discretion * Participants must be willing to undergo mandatory on-study tumor biopsies * Participant is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up * Participant must be able to swallow tablets or capsules. A participant with any gastrointestinal disease that would impair ability to swallow, retain, or absorb drug is not eligible * Participants of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required * Participants must agree to use an adequate method of contraception starting with the first dose of study therapy and for the required length of time ascribed to the assigned study drug assignment * No other prior invasive malignancy is allowed except for the following: adequately treated basal (or squamous cell) skin cancer, in situ breast or cervical cancer, any malignancy treated with a curative intent without evidence of disease recurrence for at least 6 months * Individuals must not have known active hepatitis B virus (HBV). Those who have completed curative therapy for hepatitis C virus (HCV) are eligible. HCV infection permitted but patient must be Child's Pugh A. Patients with known human immunodeficiency virus (HIV) infection are eligible if they meet all of the following 3 criteria: * CD4 counts \>= 350 mm\^3 * Serum HIV viral load of \< 25,00