Inclusion Criteria

- INCLUSION CRITERIA:

- Patients must have histologically confirmed metastatic colorectal cancer, which has
recurred or progressed following oxaliplatin- and irinotecan-based chemotherapy
regimens administered for the treatment of metastatic disease, except if the patient
was not a candidate for either agent or refused treatment with oxaliplatin or
irinotecan. The diagnosis must be confirmed by the Laboratory of Pathology at the
Clinical Center, NIH, prior to patient enrollment.

- Results of KRAS mutation analysis must be available prior to patient enrollment.

- Patients must have disease amenable to biopsy, and must be willing to undergo pre-
and post-treatment tumor biopsies.

- Patients must have completed any major surgery chemotherapy, radiation therapy, or
biologic therapy greater than or equal to 4 weeks prior to entering the study (6
weeks for nitrosoureas or mitomycin C). Patients must be greater than or equal to 2
weeks since any prior administration of a study drug in an exploratory IND/Phase 0
study. Patients must have recovered to eligibility levels from any prior surgery,
toxicity, or adverse events.

- Age greater than or equal to 18 years. Because no dosing or adverse event data are
currently available on the use of MK-2206 in combination with AZD6244 in patients
less than 18 years of age, children are excluded from this study.

- Life expectancy of greater than 3 months.

- ECOG performance status less than 2.

- Patients must have normal organ and marrow function as defined below:

- Absolute neutrophil count greater than or equal to 1,500/microL

- Platelets greater than or equal to 100,000/microL

- Total bilirubin less than or equal to 1.5 times institutional ULN

- AST /ALT less than or equal to 3.0 times institutional ULN; less than or equal
to 5.0 times institutional ULN if liver metastases

- Creatinine less than 1.5 times ULN; OR

- Measured creatinine greater than or equal to 60 mL/minute for patients with
clearance creatinine levels greater than or equal to 1.5 times ULN

- INR less than or equal to 1.4

- PTT less than or equal to 40 seconds unless due to lupus anticoagulant

- The effects of MK-2206 and of AZD6244 on the developing human fetus at the
recommended therapeutic dose are unknown. For this reason women of child-bearing
potential and men must agree to use adequate contraception (hormonal or barrier
method of birth control; abstinence) prior to study entry, for the duration of study
participation, and for 4 weeks after dosing with study medication ceases. However,
adequate contraception for male patients should be used for 16 weeks post- last dose
due to sperm life cycle. Should a woman become pregnant or suspect she is pregnant
while she or her partner is participating in this study, she should inform her
treating physician immediately. Women of child-bearing potential must have a negative
pregnancy test prior to entry.

- Patients must be able to swallow whole tablets and capsules. Tablets must not be
crushed or chewed; capsules must not be opened.

- Ability to understand and the willingness to sign a written informed consent
document.

EXCLUSION CRITERIA:

- Patients who are receiving any other investigational agents.

- Patients with known brain metastases or carcinomatous meningitis are excluded from
this clinical trial, with the exception of patients whose brain metastatic disease
status has remained stable for greater than or equal to 4 weeks after treatment of
the brain metastases, without steroids. Patients on stable doses of antiseizure
medications with no history of seizures in the past 4 weeks will be eligible.

- Poorly controlled diabetes defined as fasting blood glucose of greater than 160 mg/dL
(CTCAE Grade greater than or equal to 2) or HgA1c greater than 8%.

- QTc prolongation greater than 450 msec (male) or QTc greater than 470 msec (female)
by Bazett's formula or use of medications that may cause QTc interval prolongation. A
comprehensive list of agents with the potential to cause QTc prolongation can be
found at http://www.azcert.org/medical-pros/drug- lists/bycategory.cfm.

- Patients with clinically significant intercurrent illnesses, including but not
limited to, interstitial pneumonitis, pulmonary fibrosis, uncontrolled infection,
psychiatric illness or social situations that would limit compliance with study
requirements.

- Patients with symptomatic congestive heart failure, unstable angina, uncontrolled
cardiac arrhythmia, myocardial infarction in the past 6 months, left ventricular
ejection fraction (LVEF) less than or equal to 50%, are not eligible to participate.

- Uncontrolled hypertension (blood pressure [BP] of greater than or equal to 150/95
despite optimal therapy).

- Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g., inflammatory
bowel disease), or significant bowel resection that would preclude adequate
absorption.

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with MK-2206 and AZD6244.

- Patients currently on warfarin (Coumadin) are ineligible. Otherwise eligible patients
requiring anticoagulant treatment should have their warfarin switched to a low
molecular weight heparin such as enoxaparin injections.

- Patients on strong cytochrome P450 system inducers or inhibitors are ineligible.

INCLUSION OF WOMEN AND MINORITIES:

-Both men and women of all races and ethnic groups are eligible for this trial.