## **Core Concept**
Methotrexate is an antifolate drug used in the treatment of various cancers and autoimmune diseases. It works by inhibiting dihydrofolate reductase (DHFR), an enzyme crucial for DNA synthesis and cell replication. Resistance to methotrexate can occur through several mechanisms.

## **Why the Correct Answer is Right**
The correct answer, **C. Increased efflux of drug**, is a recognized mechanism of methotrexate resistance. Cells can develop resistance by increasing the expression of efflux transporters, such as P-glycoprotein, which pumps methotrexate out of the cell, thereby reducing its intracellular concentration and effectiveness.

## **Why Each Wrong Option is Incorrect**
- **Option A: Decreased influx of drug** - This is indeed a mechanism of resistance. However, it is not the correct answer chosen. Decreased influx occurs when there is reduced expression of the reduced folate carrier (RFC), which is responsible for transporting methotrexate into cells.
- **Option B: Increased synthesis of DHFR** - While increased synthesis of the target enzyme DHFR can contribute to methotrexate resistance by providing more enzyme for the drug to inhibit, it is not the correct answer provided.
- **Option D: Decreased polyglutamation of drug** - Methotrexate needs to be polyglutamated to be trapped inside cells and to effectively inhibit DHFR. Decreased polyglutamation can lead to resistance, but it is not the chosen correct answer.

## **Clinical Pearl / High-Yield Fact**
A key clinical pearl is that **methotrexate resistance can be overcome by using higher doses or by combining it with other drugs that can modulate its effects**. For example, leucovorin (folinic acid) can be used to rescue normal cells from methotrexate toxicity, but its use can also reduce the efficacy of methotrexate.

## **Correct Answer: C. Increased efflux of drug**